HDAC inhibitors and effects of HDAC inhibition in different models of HD.
Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the exon-1 of the huntingtin (htt) gene. The presence of mutant htt (mhtt) results in multiple physiopathological changes, including protein aggregation, transcriptional deregulation, decreased trophic support, alteration in signaling pathways and excitotoxicity. Indeed, the presence of mhtt induces changes in the activities/levels of different kinases, phosphatases and transcription factors that can impact on cell survival. Many studies have provided evidence that transcription may be a major target of mhtt, as gene dysregulation occurs before the onset of symptoms. The greatest number of downregulated genes in HD has led to test the ability of a large number of compounds to restore gene transcription in mouse models of HD. On the other hand, mhtt engenders multiple cellular dysfunctions including an increase of pathological glutamate-mediated excitotoxicity. For that reason, targeting the excess of glutamate has been the goal for many promising drugs leading to clinical trials. Although advances in developing effective therapies are evident, currently, there is no known cure for HD and existing symptomatic treatments are limited.
- HDAC inhibitors
- transcriptional dysregulation
Huntington’s disease (HD) is a progressive, fatal, dominantly inherited neurodegenerative disorder  characterized by motor and cognitive dysfunction. Neuropathologically, HD is primarily characterized by neuronal loss in the striatum and cortex  together with hippocampal dysfunction . The disease is caused by an unstable expansion of CAG repeats in the huntingtin (htt) protein . Htt is ubiquitously expressed [5, 6] and interacts with proteins that cover diverse cellular roles including apoptosis, vesicle transport, cell signaling and transcriptional regulation .
Although it is well established that the disease occurs as a consequence of an expanded polyglutamine repeats above 35 , the pathological mechanisms are not fully understood yet. Increasing evidence suggests that in addition to the gain of toxic properties, reduced htt physiological activity may render, in part, striatal neurons particularly vulnerable [8, 9]. The presence of mutant htt (mhtt) results in multiple pathophysiological changes, including protein aggregation, transcriptional dysregulation and chromatin remodeling, decreased trophic support, alteration in signaling pathways and disruption of calcium homeostasis and excitotoxicity.
Htt functions in transcription are well established. Htt has been shown to interact with a large number of transcription factors [10, 11], indicating a role of the protein in the control of gene transcription . Htt is also believed to have a prosurvival role. Several
2. Transcriptional dysregulation in HD and potential therapies
Many studies have provided evidence that transcription may be a major target of mhtt [11, 18–20], as gene dysregulation occurs before the onset of symptoms . Subsequently, a large number of studies showed transcriptional abnormalities in HD [21–23].
Initially, it was shown that mhtt establishes abnormal protein-protein interactions with several nuclear proteins and transcription factors, recruiting them into aggregates and inhibiting their activity [11, 24] ( Figure 1 ), as occurs with CREB (cyclic-adenosine monophosphate (cAMP) response element (CRE) binding protein)-binding protein (CBP) [11, 24]. On the other hand, mhtt can also fail to interact with other transcription factors ( Figure 1 ), altering their activity which could induce the repression of a large cohort of neuronal-specific genes [25, 26]. Mhtt fails to interact with repressor element-1 transcription/NRSE, so then the complex can translocate from the cytoplasm to the nucleus and bind NRSE repressing a large cohort of neuronal-specific genes, including the brain-derived neurotrophic factor (
The greatest number of downregulated genes in HD  has led to the initiation of new lines of research aimed at testing the ability of a number of compounds to restore gene transcription in mouse models of HD. However, the development of therapies targeting altered transcription faces serious challenges, as no single transcriptional regulator has emerged as a main factor of the disease. Nevertheless, potential therapeutic advances have emerged recently. Some of them include inhibition of HDAC [29, 30], compounds that directly interact with DNA , as well as drug-targeting proteins involved in the modulation of transcription [32, 33] ( Figure 1 ).
Increasing evidence indicates that CREB is essential for activity-induced gene expression and memory formation . CBP is a CREB-transcriptional coactivator that enhances CREB-mediated transcription of specific genes  and can also act as a HAT allowing gene transcription . Decreased levels of CBP due to sequestration into mhtt aggregates or increased degradation have been associated with striatal neurodegeneration in HD [20, 37]. Moreover, hippocampal-dependent cognitive deficits have been related to a reduced expression of CBP and reduced levels of histone acetylation . Consistent with deficits in striatal and hippocampal CBP function, either CBP overexpression or HDAC inhibition could represent therapeutic strategies to improve transcriptional dysregulation. HDAC inhibitors have been under study for several years ( Figure 1 ). Indeed, McCampbell et al. [20, 39] demonstrated that overexpression of CBP reduced polyglutamine-mediated toxicity in neuronal cell culture. CBP overexpression reversed the hypoacetylation phenomenon observed in polyglutamine-expressing cell which reduced cell loss. A similar effect was observed when cells were treated with HDAC inhibitors demonstrating that altered protein acetylation in neurons could play an important role in polyglutamine diseases . Pharmacological treatments using the HDAC inhibitors, sodium butyrate and suberoylanilide hydroxamic acid (SAHA), significantly improve survival, motor performance, modulate transcription and delay neuropathology in the R6/2 transgenic mouse model of HD [29, 40]. In this line, benzamide-type HDAC inhibitor 4b, ameliorated motor and behavioral symptoms and corrected transcriptional abnormalities in R6/2 and N171-82Q transgenic mice [30, 41]. Moreover, 4b treatment induced DNA methylation changes that were inherited to the next generation. First filial generation offspring from drug-treated male HD transgenic mice shows significantly improved HD disease phenotypes compared with the offspring from vehicle-treated male HD transgenic mice . Likewise, administration of the HDAC inhibitor trichostatin A (TSA) rescues hippocampal-dependent recognition memory deficits and increases the transcription of selective CREB/CBP target genes in HdhQ7/Q111 mice . Moreover, more physiological approximations to increase CBP levels and reduce HDAC activity have been recently suggested. Moreno et al. observed that dietary restriction not only induces the expression of
|1,2,3,4,5,7,8 and 9||Valproic acid||N171-82Q mouse and YAC128||↑ Survival|||
|Improve motor performance|
|↑ BDNF and Hsp70 levels|
|1,2,3,4,5,7,8 and 9||Sodium butyrate||R6/2 mice||↑ Survival|||
|Improve motor performance|
|↑ Body weight|
|1,2,3,4,5,7,8 and 9||Phenyl butyrate||N171-82Q mouse||↑ Survival|||
|↓ Brain atrophy|
|↑ Proteasome pathway|
|↓ Caspase activation|
|All HDAC||TSA||HdhQ7/Q111||↑ CREB target genes|||
|Rescue memory deficits|
|All HDAC||SAHA or vorinostat||R6/2 mice||Improve motor performance||[29, 191]|
|↑ BDNF levels|
|↓ mhtt cortical aggregates|
|3||RGFP966 (benzamide)||N171-82Q mouse||Improve motor performance|||
|↓ Striatal degeneration|
|1 and 3||HDACi 4b||N171-82Q mouse||Improve phenotype||[41, 42, 30]|
|and R6/2 mice||↓ mhtt aggregates|
|Sirtuin||Nicotinamide||R6/1 mice||↑ BDNF and PGC-1α levels|||
|Improve motor performance|
|Sirtuin (activation)||Resveratrol||Rescue mhtt toxicity|||
Inhibition of HDAC by 4b was shown not only to affect transcription but also posttranslational modification processes which can influence aggregate formation . On the other hand, inhibition of HDAC4 resulted in a delay in cytoplasmic aggregate formation, together with restored Bdnf transcript levels, rescued neuronal function and improved phenotype in HD mouse models, pointing HDAC4 as a novel strategy for targeting htt aggregation . This potential role of acetylation in mhtt degradation adds importance to HDAC inhibitors as a therapeutic target in HD pathology. These promising results have led to the enrollment of HD patients in clinical trials as HDAC inhibitors are safe and well tolerated . However, these compounds can cause some side effects . It is therefore important to improve our knowledge, to be able to generate effective and specific HDAC inhibitors. Sirtuins belong to the class III of HDAC enzymes and have been a recent focus of therapeutic development for neurodegenerative disease . Interestingly, activation, instead of inhibition of sirtuins, with their ligand resveratrol, was found to be neuroprotective in HD worms [48, 49]. Resveratrol and other potent activators of sirtuins have been used in preclinical trials, but further experiments need to be performed to assess the therapeutic potential of these enzyme targets in HD .
Apart from HDAC, other drugs like anthracyclines could produce a beneficial effect in promoting transcription in HD. Anthracyclines are DNA topoisomerase II inhibitors and are broadly used in cancer chemotherapeutics . A novel function of these molecules has recently been identified. Anthracyclines can induce histone eviction from the DNA  making it more accessible to the transcriptional machinery and maybe being able to counteract the transcriptional inhibition that occurs in HD. Nevertheless, side effects promoted by these treatments should be taken in high consideration.
When thinking about potential genes downregulated in HD, Bdnf is considered to be one of the principal focuses of attention. BDNF has emerged as the major regulator of neuronal development, synaptic plasticity and neuronal survival and also a key molecular target for drug development in HD [9, 52]. When targeting BDNF deficits in HD, different approximations have been developed. Several evidence suggest that HDAC inhibitors induce the expression of multiple downstream targets that might work collectively to elicit neuroprotective effects, like neurotrophins. For instance, it was observed that BDNF was induced by treatment with valproic acid, sodium butyrate, or TSA [53, 54]; thus, it is conceivable that restoring BDNF to their normal levels is part of the molecular mechanism underlying the beneficial effects elicited by HDAC inhibition in various HD models. Moreover, inhibition of HDAC6 increases vesicular transport of BDNF in a similar way to the cystamines, compensating for the transport deficit in HD [48, 55]. Focusing on BDNF deficits, identification of compounds or small molecules capable of antagonizing the repressive action of REST/NRSF in gene transcription has begun and represents a rational and promising target to break down with transcriptional repression present in HD [33, 56]. To this aim, Cattaneo’s laboratory has developed a cell-based reporter assay to monitor re1 activity in brain cells and identify compounds that specifically upregulate BDNF expression in HD . It has also been identified a benzoimidazole-5-carboxamide derivative that inhibited REST silencing in an RE1-dependent manner, the X5050 compound. X5050 targets REST degradation and produces an upregulation of neuronal genes targeted by REST. This activity was confirmed in human-induced pluripotent stem cells derived from an HD patient and in mice with quinolinate-induced striatal lesions .
3. Breaking signaling pathways
Protein kinases/phosphatases regulate most aspects of normal cellular function. Inhibitory or stimulatory actions at these signaling pathways strongly affect neuronal function by altering the phosphorylation state of target molecules and by modulating gene expression . In fact, several kinases and phosphatases have been reported to be altered in HD patients and animal models. Some of these kinases altered in HD are closely related to synaptic plasticity, cell survival and transcriptional regulation such as cAMP-dependent protein kinase (PKA) , the kinase Akt [60, 61], the mitogen-activated protein kinases (MAPKs) [62–64] and kinases downstream MAPK pathway [65–67]. Furthermore, also several phosphatases are altered in HD mouse models. Some examples are the phosphatase calcineurin [68, 69], the PH domain and leucine-rich repeat protein phosphatases (PHLPP)  and the striatal-enriched protein tyrosine phosphatase (STEP) . Therefore, therapies with potential to modulate cell signaling pathways could provide protection against neurodegeneration [70, 71].
3.1. Kinases and downstream targets
3.1.1. Extracellular signal-regulated kinase (ERK)
Transcription of target genes is controlled by a series of transcription factors, which are, in turn, regulated by a number of kinases. Among the kinases implicated in HD, those involving ERK signaling cascades are of particular interest ). ERK 1/2 is a strong antiapoptotic and prosurvival mediator. Moreover, ERK 1/2 downregulation is linked to neurodegenerative conditions [75, 76]. Recent studies using HD mouse and cellular models provide strong evidence that activation of ERK has the neuroprotective effect, while the specific inhibition of ERK activation enhances cell death [62, 64, 71]. Supporting the neuroprotective role of ERK activation, we have previously reported that enhanced activity of the ERK pathway may participate in the reduced neuronal loss observed after quinolinic acid (QUIN) injection in R6/1 mice ( Figure 2 ) . When injected with QUIN, both WT and R6/1 mice display an increase in the phosphorylation of ERK levels, but activation of ERK was more prolonged in resistant R6/1 mice than in susceptible controls . Moreover, inhibition of ERK has been found to block the induction of BDNF-regulated genes , thus implicating this pathway as an important regulator of BDNF-induced transcription. For that reason, the ERK pathway has been investigated as a potential neuroprotective modulator of HD pathology [62, 64]. In this context, it has been suggested that reduced levels of ERK in the cortex of HD models can lead to increased cell dead and reduction in the expression of BDNF. Then, less BDNF is available to striatal neurons, which activates, in response, compensatory mechanisms increasing the expression of ERK ( Figure 2 ) .
Drugs, targeting the ERK pathway, may provide a basis for developing disease modifying therapeutic interventions for HD. Neuroprotective compounds identified using a neuronal cell culture model of HD in combination with a library of 1040 biologically active compounds were shown to prevent cell death by activation of ERK and Akt signaling, with the ERK pathway playing the major role . More recently, results from another screening showed that pizotifen caused transient ERK activation in an immortalized striatal cell line expressing mhtt (STHdhQ111/Q111) and inhibition of ERK activation increases cell death in this
3.1.2. p90 ribosomal s6 kinase (Rsk)
These aforementioned studies suggest that pharmacological intervention at the level of ERK activation or downstream ERK may be an appropriate approach in HD therapy. Most common kinases phosphorylated by ERK1/2 include Rsk and the mitogen- and stress-activated protein kinases (MSK) [84, 85]. In this context, we have reported changes in the expression of Rsk related to the presence of motor symptoms in HD. Meanwhile, an increase in Rsk protein levels was observed in the striatum of HdhQ111/Q111 and R6/1 mice at presymptomatic stages of the disease , they were downregulated in the same models when motor symptoms were present , indicating that Rsk downregulation is associated with the presence of motor impairment, the main clinical feature in HD . Similarly, Rsk levels were increased in STHdhQ111/Q111 cells , but strongly decreased in postmortem caudal and putamen samples from HD patients . Knockdown experiments indicated that Rsk activity exerted a protective effect against mhtt-induced cell death in STHdhQ7/Q7 cells transfected with mhtt and overexpression of Rsk in R6/1 mice at the onset of motor sympt oms rescues motor impairment, enhanced expression of synaptic markers and increased expression of genes related to synaptic plasticity, such as cfos and egr1 [65, 67]. We also observed that downregulation of Rsk was due, at least in part, to the depletion of BDNF in HD striatum suggesting that Rsk could be a downstream effector of BDNF function. These results place Rsk as a new element regulating striatal alteration that leads to motor phenotype in HD, making it a good target for neuroprotective therapies in HD.
Different drugs could be used to increase Rsk activation. As a downstream target of ERK , activation of ERK pathway could result in an activation of Rsk as an effector. In this line, previously proposed drugs could be also useful in promoting Rsk activation. As for ERK activation, clozapine treatment also increases levels Rsk phosphorylation in the cortex and striatum in an ERK-dependent manner, meanwhile Rsk activation by olanzapine and haloperidol is not concomitant with ERK signaling . Although the Rsk pathway can be activated by increased ERK activity, more research focusing on specific drugs targeting Rsk should be carried out.
3.1.3. Activation of transcription factors: CREB and Elk-1
ERK 1/2 cannot only phosphorylate different kinases, but also some transcription factors such as CREB ( Figure 2 ) [86, 87]. But CREB can also be phosphorylated by other kinases as Rsk [88–90] and PKA . Once activated, CREB interacts with CBP and CREB-mediated gene expression is induced . CREB is a widely expressed transcription factor known to mediate stimulus-dependent expression of genes critical for plasticity, growth and survival of neurons . Activation of CREB is necessary for synaptic transmission  and CREB-mediated gene expression is sufficient for the survival of multiple neuronal subtypes [95, 96]. CREB may exert this prosurvival effect by regulating the transcription of prosurvival factors, such as
Different studies observed that CREB signaling is compromised in different mouse and cellular models of HD and in human HD samples, where the expression of mhtt induces aggregation of its coactivator CBP ( Figure 2 ) [11, 28, 98], reduces the levels of cAMP  and downregulates CRE-mediated transcription of numerous genes . This decrease in CREB-induced transcriptional activity is believed to contribute to HD pathogenesis . One of the genes regulated by CREB is
The beneficial effect of restoring CREB phosphorylation has been observed by us and others in both excitotoxic and genetic mouse models of HD [100, 101]; thus pathways targeting CREB activation can also lead to an increase in BDNF together with cognitive improvements in HD models . Furthermore, regulation of possible downstream effectors of BDNF function also shows clearly motor improvements together with a restoration of CREB-mediated gene transcription and expression of synaptic markers in R6/1 mouse model of HD [102, 103].
ERK1/2 can also phosphorylate the transcription factor Elk-1, which, together with CREB, is considered to be one of the most important transcription factors in neurons [104, 105]. In the cortex, Elk-1 is activated after QUIN-induced lesion and has the capacity to prevent excitotoxic cell death . Increased phosphorylation of ERK-activated transcription factors, such as Elk1, has been correlated with increased ERK phosphorylation in R6 striatum [107, 108]. However, the expression of
3.2. Regulating CAMP
To increase activation of CREB, it is also important to take into account the levels of cAMP. The major kinase that is in charge of CREB activation is PKA, which in turn needs cAMP to be activated . The cAMP signaling pathway has a key role in the neurobiology of learning and memory and therefore could serve as a target for cognitive enhancers and to reduce memory deficits in HD. In support to this idea: (1) reduced levels of cAMP were reported in the cerebral spinal fluid of symptomatic HD patients  and (2) forskolin, which stimulates adenylyl cyclases to produce cAMP from ATP, was able to ameliorate mhtt-induced phenotypes in PC12 cells . Reduced levels of cAMP were also observed in STHdhQ111/Q111 striatal cells together with a decreased nuclear localization of CBP . Activation of cAMP/PKA signaling by forskolin restored a nuclear CBP expression in the mutant striatal cells  and could partially rescue the loss of neurite outgrowth and cell death due to reduced CRE-mediated transcriptional activity .
3.2.1. Role of phosphodiesterases
Different studies  suggest that phosphodiesterase (PDE) inhibitors might be good candidates for enhancing CREB activation. PDE inhibitors prevent the breakdown of cAMP to 5′-AMP, prolonging the activation of protein kinases that promote phosphorylation of CREB . It has been shown that the expression of different PDEs is altered in the striatum [115, 116] and hippocampus  of HD mouse models. The use of drugs that maintains CREB phosphorylated, like the specific PDE4 and 10 inhibitors rolipram and T10, decreases striatal cell loss after the injection of QUIN in an excitotoxic model of HD [100, 117]. Following this research, the same group reported that administration of rolipram in R6/2 mice enhanced the expression of both phosphorylated CREB and BDNF in striatal neurons and ameliorated neurodegeneration, decreased mhtt inclusions preventing the sequestration of CBP, reduced microglia activation and rescue motor function [118, 119]. Likewise, beneficial effects of PDE inhibition on cognitive function were also observed in the hippocampus of HD mouse model . We recently observed that papaverine, which is considerably selective for PDE10A, could improve spatial and object recognition memories in R6/1 mice and significantly increase phosphorylation of CREB and cAMP levels in the hippocampus .
Although PDE10A has been proposed as a therapeutic target for HD based on the observation that pharmacologic inhibition of PDE10A in transgenic HD mice significantly improved behavioral and neuropathologic abnormalities [101, 119], some conflicts appear when focusing on HD patients. Earlier work had shown that striatal PDE10A levels in HD mice already decline to minimal levels before onset of motor symptoms [115, 116]. In humans, decreased PDE10A levels were found in postmortem striatal tissue  and in PET studies from Huntington’s disease patients with significant striatal atrophy  and premanifest Huntington’s disease gene carriers [121, 122]. It is unclear how the alteration of PDE10A expression is related to the neuropathological out-standing networks. Depletion of PDE10A in HD striatum would at first sight seem hard to reconcile with a beneficial effect of PDE10A inhibitors in HD. However, a recent study reported a dramatic increase in PDE10A levels in the perikarya of striatal medium spiny neurons  and moreover, we did not observe changes in the expression of this protein in the hippocampus of R6/1 mice compared to controls . Taking together all these results, it is important to determine whether PDE10A levels are affected in HD patients and in
3.2.2. Role of G protein couple receptors
G protein-coupled receptors (GPCRs) constituted a large family of receptors coupled to G proteins that activated two main signaling pathways: cAMP and phosphatidylinositol pathways . GPCRs are involved in many diseases and are also the target of approximately 40% of all modern medicinal drugs .
In order to increase the levels of cAMP, molecules targeting GPCRs could be useful. Depending on the subunit of G protein that the receptors are coupled, they can activate (Gαs) or inactivate (Gαi/o) adenylate cyclases . Therefore, drugs targeting the activation of Gαs-coupled receptors or the inhibition of Gαi/o-coupled receptors would result in an increase in the levels of cAMP and probably in turn an increase in the activation of CREB. In line with this idea, we have recently demonstrated that fingolimod (FTY720) treatment improves synaptic plasticity and memory in the R6/1 mouse model of HD, through regulation of BDNF signaling . FTY720 targets GPCRs Gαi/o SP1 receptor and inhibits it . Between the different effects of SP1 receptor activation there is a reduction on cAMP as Gαi/o inhibits adenylate cyclases . Therefore, inhibition of SP1 receptor could result in increased levels of cAMP. Indeed, FTY720 treatment increased cAMP levels and promoted phosphorylation of CREB in the hippocampus of R6/1 mice .
Another approximation to increase cAMP levels is inducing the activation of Gαs-coupled receptor. Prostaglandin (PG) receptors are well-known GPCRs . EP2 prostaglandin receptor is known to stimulate cAMP and activation of the transcription factor CREB . EP2 receptor activation is associated with neuroprotection and hippocampal-dependent synaptic plasticity  and can lead to the induction of BDNF [102, 131]. In terms of HD, we have recently shown that chronic treatment of R6/1 mice with misoprostol, an EP2 receptor agonist, ameliorated hippocampal-dependent long-term memory deficits in these animals . Importantly, misoprostol treatment promoted the expression of hippocampal BDNF and increased cAMP levels, together with a recovery in the expression of different synaptic markers. All these data suggest that mhtt leads to alterations of CRE-mediated gene transcription and reinforce the idea of a beneficial effect of increasing gene expression mediated by CREB could be a good therapeutic approach in HD.
4. Cycle of neurotoxicity
Ultimately, excitotoxicity contributes to neuronal degeneration in many acute as well as chronic central nervous system diseases . Polyglutamine expansion produces a hyperactivation of N-methyl-D-aspartate receptor (NMDAR and kainite receptors) ; stabilizes NMDA receptors in the postsynaptic membrane ; inhibits the uptake and release of glutamate at the synapses ; and can also sensitize the inositol (1,4,5)-triphosphate receptor type 1 located in the membrane of the endoplasmatic reticulum . In addition, mhtt can contribute to excitotoxicity by decreasing the expression of the major astroglial glutamate transporter (GLT-1) , which reduces the glutamate uptake ( Figure 3 ) . All these alterations promote glutamate-mediated excitotoxicity by a massive increase of intracellular Ca2+, which affect the calcium homeostatic mechanism  and lead to deleterious consequences. Imbalance in the calcium homeostasis has been previously reported in different HD mice [140–142] that it is in agreement with consistent changes in the expression levels of many Ca2+ signaling proteins . Moreover, different proteins involved in neuronal Ca2+ signaling have been proposed as attractive targets for developing therapies for HD . Excitotoxicity and mhtt expression also promote the activation/inhibition of several pathways regulated by different kinases and phosphatases [74, 145]. In the following lines, we will review some of the mechanism implicated in this excitotoxic process that occurs in HD, together with the prosurvival mechanism activated in HD brains to fight against this process. Moreover, we will discuss about potential and new state-of-the-art therapies to fight neurodegeneration and reduce excitotoxicity.
4.1. Fighting glutamate
4.1.1. NMDA receptors
Alterations in proteins involved in glutamatergic signaling have been reported in mouse models of HD [146, 147]. Since the main hypothesis underlying striatal neurodegeneration in HD has been excitotoxicity, due in part to increase in glutamate release, NMDA receptors were the first glutamate receptors studied. At early stages of the disease, when cognitive and plasticity alterations are detected, no changes in the protein levels of any NMDAR subunit are observed in the striatum and hippocampus of HD mouse models [148–150]. Conversely, HD mouse models do not respond to intrastriatal NMDAR agonists ( Figure 2 ) [141, 149, 151]; which support the idea that signaling downstream the receptor is affected in HD  and contributes to synaptic plasticity impairment. Not only the expression of these receptors is important, but also their location. Stimulation of synaptic NMDAR conveys the synaptic activity-driven activation of the survival-signaling protein ERK and triggers an increase in nuclear calcium, leading to the activation of the transcription factor CREB and the production of the survival-promoting protein BDNF . In contrast, global or extrasynaptic NMDAR stimulation decreases ERK and CREB activation and BDNF production, promoting cell death ( Figure 3 ) .
4.1.2. Glutamate transporters
On the other hand, not only glutamate receptors but also glutamate transporters are altered in HD, such as the vesicular glutamate transporter 1 (VGluT1)  that contributes to the imbalance of glutamate in neurons could play a role in cell dysfunction in HD. Presynaptic expression of VGluT1 contributes to the proper expression of other synaptic proteins and reduced levels of this glutamate transporter, as occurs in the striatum of R6 mice [154, 155], can disrupt cortico-striatal synaptic transmission [154, 156]. The expression of glutamate transporters is also altered in glial cells. GLT-1 is the major molecule responsible for the clearing of glutamate from synaptic cleft , making it an attractive therapeutic target. Reduced mRNA levels of GLT-1 and decreased glutamate uptake have been described in HD postmortem brains  as well as in R6/2 mice , suggesting decreased glutamate removal at synapses in HD. Moreover, alterations in the palmitoylation of this transporter were detected, which can alter its function . In addition, strategies aiming at the upregulation of GLT-1, like ceftriaxone treatment , attenuate some behavioral alterations in the R6/2 mice model ( Figure 3 ) .
4.1.3. Strategies to decrease glutamate excitotoxicity
Drugs inhibiting glutamate neurotransmission [161, 162], glutamate antagonists  and blockade of NMDAR [164, 165] have been used for the first time to attempt for blocking the excess of glutamate at the synapse. Riluzole and amantadine are two antiglutamatergic therapies that have been investigated in rigorous trials in HD . Moreover, riluzole is already marketed for the treatment of amyotrophic lateral sclerosis. Riluzole is a drug that inhibits glutamate release and the current evoked by the stimulation of excitatory amino acid receptors . Treatment of R6/2 mice with riluzole showed positive effects in reducing the progression of neurological abnormalities in this mice model of HD . Specific blockade of NMDAR has been also extensively studied, but accuracy has to be taken into account. Drugs like memantine are shown to inhibit NMDAR [164, 165, 167], but their beneficial effects depend on the right dose. At high concentrations, memantine blocks synaptic and extrasynaptic NMDAR, inducing neuronal death, as NMDAR once at the synapse can activate prosurvival pathways . When used in a lower dose, memantine can specifically block extrasynaptic NMDAR producing a potential therapeutic effect in mouse models of HD [164, 165]. A new technique to combat the glutamate exposure developed recently is the blood glutamate scavenging system (Braintact) [168, 169]. Braintact is developing a platform solution that overcomes the excess glutamate level in blood by using a new approach developing drugs that remain in the blood circulation and boost a natural mechanism that reduces glutamate levels in the bloodstream and leads to lowering of glutamate concentrations in the brain ( Figure 3 ).
Although common strategy is to treat with NMDA glutamate antagonist for reducing excitotoxicity, their clinical viability has not been proven . Some agents showed efficacy in terms of motor dysfunction, but no treatment has been identified as appropriated. Moreover, many present treatments considerable side effects or effects in cognitive improvement were not even considered. Therefore, there is a need to continue the research on antiglutamatergic drugs in HD for the treatment of excitotoxicity. Also cellular pathways and drugs trying to enhance or inhibit these cellular pathways related to survival will be discussed further in this section.
4.2. Role of kinases
Increasing our understanding on the pathways behind the excitotoxic events and neuronal dead occurring in HD is necessary in order to identify targets downstream glutamate receptors cascade that may represent useful therapeutic strategies do reduce or halt neuronal dysfunction. Alterations in numerous signal transduction pathways and aberrant activity of specific kinases have been identified in multiple cell and mouse models of HD, as well as in human HD brain. Unbalanced activities within these pathways provide a potential mechanism for many of the pathological events associated with HD. Aberrant kinase signaling regulation in HD has a wide range of effects on multiple pro and antiapoptotic kinases, resulting in the activation of compensatory mechanisms to fight excitotoxicity or prodeath mechanisms triggered by excitotoxicity .
The ERK pathway is a strong mediator of antiapoptotic and prosurvival signaling. Although both protective and deleterious roles have been proposed for ERK activation in neuronal cells , recent studies using mhtt-expressing cells provide strong evidence that activation of ERK is neuroprotective, while specific inhibition of ERK enhances cell death . The phosphorylation of ERK activates neuroprotective factors [62, 107] and inactivates proapoptotic mediators by phosphorylation . Data derived from cell culture experiments showed that ERK is activated in response to mhtt and increases cell survival . The ERK pathway is also upregulated in several transgenic animal models of HD. Significant ERK activation was observed in the striatum of R6/1 and R6/2 mouse ( Figure 2 ) [64, 107]. The timing of ERK activation in HD mice supports the hypothesis that the ERK pathway might not be involved in a primary pathological process, but rather that it is a compensatory mechanism activated in response to mhtt and could participate in delaying striatal cell death because R6 mice show no significant cell loss . Accordingly and as previously mentioned, ERK pathway activation in response to mhtt may participate in the reduced neuronal loss observed after QUIN injection in R6/1 mice ( Figure 2 ) . Moreover, changes in ERK levels and activation can modulate transcription in HD what triggers, in part, the neuroprotective role of ERK mediated by its downstream effectors.
Checking on the ERK mechanism along the different sections, we can conclude that ERK has a prosurvival role in the presence of mhtt, which can be achieved by the activation/inactivation of different proteins promoting survival and transcriptional regulation of protective genes. Therefore, ERK activation might provide a novel therapeutic approach to prevent neuronal dysfunction in HD.
The AKT signaling pathway has been extensively characterize in models of HD and its activation is considered to be antiapoptotic and neuroprotective in different models of acute and chronic neurodegeneration [72, 173]. A primary mechanism of AKT-mediated neuroprotection is by its phosphorylation and inactivation of proapoptotic machinery [61, 72, 174].
In HD, the AKT pathway has been proposed as a crucial neuroprotective pathway, because it is one of the serine/threonine kinases that phosphorylate Ser421 of mhtt, attenuating its toxicity . Activation of the AKT pathway has been determined in several cells and mouse models of HD. Increased levels of phosphorylated AKT were observed in the striatum of full-length and exon-1 mouse models and also in striatal cells expression mhtt [61, 72]. We observed that enhanced AKT signaling correlates with decreased expression of PH domain leucine-rich repeat protein phosphatase (PHLPP), a phosphatase that dephosphorylates AKT ( Figure 2 ) . PHLPP1 protein levels were reduced in the striatum of HdhQ111/Q111, R6 and Tet/HD94 mouse models of HD as well as in the putamen of HD patients. In addition, we showed that intrastriatal QUIN injection in R6/1, but not in control, mice upregulates the phosphorylated AKT protein levels, which can contribute to the absence of striatal cell death observed in these animals after an excitotoxic injury [61, 151]. This increase in the phosphorylated AKT is still detected at later stages of the neurodegenerative process, offering together with phospho-ERK, a mechanistic explanation to the small amount of neuronal death observed in these HD models ( Figure 2 ). In accordance with our results, AKT prevents neuronal death induced by mhtt  and increasing AKT expression has beneficial effects on Drosophila models of HD . Thus, on the basis of these results, it is not too daring to suggest that use of therapeutic approaches focusing on AKT prosurvival pathway could delay neuronal death in HD.
4.3. Role of phosphatases
Concomitantly to kinases, several Ser/Thr protein phosphatases activate to counteract the effect of kinases. They are of particular interest in this respect as several phosphatases are altered in HD mouse models  and, most importantly, in the caudate/putamen of HD patients . Many of these altered phosphatases in HD play a role in memory and plasticity phenomena and then this imbalance likely contributes to synaptic alterations and cognitive impairment in HD.
4.3.1. Striatal-enriched protein tyrosine phosphatase (STEP)
Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase involved in neuronal signal transduction. STEP is enriched in the striatum and plays an important role in synaptic plasticity through the opposition to synaptic strengthening . We and others recently reported reduced STEP protein levels in the striatum and increased inactivity in different HD mouse models . Reduced STEP activity in HD can lead to an increase in the activity of the NMDAR . Additionally, STEP has been implicated in susceptibility to cell death through the modulation of ERK1/2 signaling pathway, as we have previously reviewed . The STEP pathway is severely downregulated in the presence of mhtt and participates in compensatory mechanisms activated by striatal neurons that lead to resistance to excitotoxicity ( Figure 2 ) . When injected with QA, R6/2 mice displayed a greater increase in STEP inactivation compared to WT together with decreased neuronal death, but overexpression of STEP in R6/2 animals increased QUIN-induced cell death . Moreover, it has been suggested that an increase in STEP activation at the synapse in YAC128 mice together with calpain activation contributes to altered NMDAR localization (increased extrasynaptic localization of GluN2B receptors) and increases excitotoxicity .
In order to select STEP as a potential therapeutic target in HD different aspects have to be taken in consideration. In HD, STEP downregulation is initially neuroprotective to mhtt-induced glutamate excitotoxicity , but a decrease in synaptic plasticity and cognitive impairment still occurs. On the other hand, increased STEP activation produces alterations in the trafficking of NMDA and AMPA receptors, dephosphorylating them and producing an excessive internalization of these receptors which decreases synaptic plasticity . On the basis of this evidence, a suitable expression of STEP might be a good therapeutic strategy in different neurodegenerative diseases. Pharmacological inhibition of STEP by a recently discovered inhibitor, TC-2153, reversed cognitive deficits in a mouse model of Alzheimer’s disease, where STEP levels are increased . But the effect of STEP activation is still not clear in a model like R6/1 mice, where STEP levels are reduced.
The role of protein phosphatases in the cascade of events triggered during excitotoxic cell death has not been extensively studied, but some protein phosphatases, such as Ca2+-dependent calcineurin, were found to contribute to excitotoxicity (because its inhibition is neuroprotective ). Calcineurin is a ser/thr protein phosphatase activated physiologically by calcium/calmodulin and it is highly expressed in the brain . Calcineurin plays an important role in synaptic plasticity and learning and memory . Interestingly, it is enriched in MSNs  and thus variations in its expression levels/activity can seriously alter their function. Some studies have shown that activation of calcineurin promotes apoptosis and pharmacological inhibition of calcineurin reduces the activation of excitotoxic molecules and decreases cell death after different toxic insults [184, 185].
Calcineurin levels are reduced in R6 and Tet-HD94 mice striatum [19, 69] and lower calcineurin activity has been shown in the striatum of YAC128 mice at 12 months of age ( Figure 2 ) . Inhibition of calcineurin with FK-506 drastically reduced cell death in an excitotoxic model of HD . Moreover, calcineurin levels were downregulated during the progression of the disease in R6/1 mice and the induction of calcineurin after QUIN injection in these excitotoxicity-resistant mice  was lower than that in control animals . These finding suggested that altered calcineurin activity contributes to the excitotoxic resistance observed in R6/1 mouse models ( Figure 2 ). On the contrary, in HdhQ111/Q111 mice calcineurin activity was shown to be increased in the cortex  and higher expression and activity of calcineurin was also observed in STHdhQ111/111 cells . These cells presented increased vulnerability to NMDAR stimulation, which was associated with higher calcineurin protein levels and activity  ( Table 2 ).
|Model||Calcineurin change||Age||Susceptibility to excitotoxicity||Age||Reference|
|YAC128 primary cortical neurons||Not reported||Increased|||
|YAC72 primary striatal neurons||Not reported||Increased|||
|Exon-1 mouse models||R6/1||Decreased||16 weeks||Decreased||8 weeks||[69, 141]|
|R6/1: BDNF−/+||Decreased||12 weeks||Decreased||12 weeks||[69, 150]|
|R6/2||Decreased||10 weeks and earlier||Decreased||3 weeks||[141, 195]|
|Tet/HD94||Decreased||22 months||Not reported|||
|N171-82Q||Not reported||Decreased||15 weeks|||
|Full-length models||YAC72||Not reported||Increased||6 and 10 months|||
|YAC128||No change||3 months||Increased||1.3–6 months||[186, 196]|
|Reduced||12 months||Decreased||10–18 months||[186, 21]|
|Knock-in models||HdhQ111/Q111||Increased||12 months||Not reported|||
|HdhQ7/Q111||Increased||12 months||Not reported|
|FVB/CAG140−/+||Not reported||Decreased||12 months|||
|FVB/CAG140+/+||Not reported||Decreased||4 months|
|C57Bl/6/CAG140−/+||Not reported||Decreased||4 months|
|C57Bl/6/CAG140+/+||Not reported||Decreased||4 months|
However, controversial data have been reported about the role of calcineurin in HD. Although decreased calcineurin activity increases resistance to excitotoxicity  and high levels of calcineurin increase mhtt toxicity [68, 186, 187], it has been shown that inhibitors of calcineurin accelerates the neurological phenotype in R6/2 mice , which are resistant to excitotoxicity . Moreover, decreased calcineurin activity appears when pathological symptoms are present in these animals and not in presymptomatic stages , suggesting a dual role of calcineurin during the progression of the disease and a possible involvement of this protein in the striatal neuronal dysfunction. Therefore, like it is occurring with STEP, it is reasonable to suggest that a therapy targeted to maintain normal levels of calcineurin could represent a good approach to delay neuronal dysfunction in HD.
As we have seen in this chapter, many pathways are interconnected and related between them, even making a “cycle.” This “cycle” could be used for developing therapies that maybe targeting one or several proteins which can modify different pathogenic events. As an example, when increasing activation of some kinases, excitotoxicity can be counteracted and at the same time promote the activation of transcription factors that can burst transcription. Then, different expressed genes can contribute to further fight against excitotoxicity completing the “cycle.” But, the development of therapies targeting altered transcription or modulation of cell signaling pathways face difficult challenges as, nowadays, no single transcriptional regulator has been identified as a main player of the disease. Nevertheless, potential therapeutic advances have recently emerged. Some of them include the inhibition of HDAC, compounds that directly interact with DNA and drugs targeting proteins involved in the modulation of transcription, representing promising therapies to protect against neurodegeneration. Also drugs inhibiting glutamate/NMDAR neurotransmission or glutamate scavenging systems have been used as a first attempt to block the excess of glutamate at the synapse. Altogether, these findings show us that although HD is a disease cause by a single gene mutation, multifactorial drug treatments could be applied in order to reduce or delay the symptoms and open a wide spectrum of research fields to reach the final cure to this de
Financial support was obtained from the University of Girona (MPCUdG2016/036). The authors declare that they have no competing interests.
Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA and et al. Homozygotes for Huntington's disease. Nature. 1987; 326:194–197. DOI: 10.1038/326194a0
Vonsattel JP and DiFiglia M. Huntington disease. J Neuropathol Exp Neurol. 1998; 57:369–384.
Spargo E, Everall IP and Lantos PL. Neuronal loss in the hippocampus in Huntington's disease: a comparison with HIV infection. J Neurol Neurosurg Psychiatry. 1993; 56:487–491.
HDCRG. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993; 72:971–983. DOI: 0092-8674(93)90585-E
Ferrante RJ, Gutekunst CA, Persichetti F, McNeil SM, Kowall NW, Gusella JF, MacDonald ME, Beal MF and Hersch SM. Heterogeneous topographic and cellular distribution of huntingtin expression in the normal human neostriatum. J Neurosci. 1997; 17:3052–3063.
Trottier Y, Devys D, Imbert G, Saudou F, An I, Lutz Y, Weber C, Agid Y, Hirsch EC and Mandel JL. Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nat Genet. 1995; 10:104–110. DOI: 10.1038/ng0595-104
Harjes P and Wanker EE. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci. 2003; 28:425–433. DOI: S0968-0004(03)00168-3 [pii];10.1016/S0968-0004(03)00168-3
Cattaneo E, Zuccato C and Tartari M. Normal huntingtin function: an alternative approach to Huntington's disease. Nat Rev Neurosci. 2005; 6:919–930. DOI: 10.1038/nrn1806; nrn1806 [pii]
Zuccato C and Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol. 2009; 5:311–322. DOI: 10.1038/nrneurol.2009.54; nrneurol.2009.54 [pii]
Kegel KB, Meloni AR, Yi Y, Kim YJ, Doyle E, Cuiffo BG, Sapp E, Wang Y, Qin ZH, Chen JD, Nevins JR, Aronin N and DiFiglia M. Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein and represses transcription. J Biol Chem. 2002; 277:7466–7476. DOI: 10.1074/jbc.M103946200;M103946200 [pii]
Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE and Thompson LM. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A. 2000; 97:6763–6768. DOI: 10.1073/pnas.100110097;100110097 [pii]
Cha JH. Transcriptional dysregulation in Huntington's disease. Trends Neurosci. 2000; 23:387–392. DOI: S0166-2236(00)01609-X [pii]
Leavitt BR, Guttman JA, Hodgson JG, Kimel GH, Singaraja R, Vogl AW and Hayden MR. Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo. Am J Hum Genet. 2001; 68:313–324. DOI: S0002-9297(07)64084-1 [pii];10.1086/318207
Leavitt BR, Van Raamsdonk JM, Shehadeh J, Fernandes H, Murphy Z, Graham RK, Wellington CL, Raymond LA and Hayden MR. Wild-type huntingtin protects neurons from excitotoxicity. J Neurochem. 2006; 96:1121–1129. DOI: 10.1111/j.1471-4159.2005.03605.x; JNC3605 [pii]
Rigamonti D, Bauer JH, De-Fraja C, Conti L, Sipione S, Sciorati C, Clementi E, Hackam A, Hayden MR, Li Y, Cooper JK, Ross CA, Govoni S, Vincenz C and Cattaneo E. Wild-type huntingtin protects from apoptosis upstream of caspase-3. J Neurosci. 2000; 20:3705–3713. DOI: 20/10/3705 [pii]
Rigamonti D, Sipione S, Goffredo D, Zuccato C, Fossale E and Cattaneo E. Huntingtin's neuroprotective activity occurs via inhibition of procaspase-9 processing. J Biol Chem. 2001; 276:14545–14548. DOI: 10.1074/jbc.C100044200;C100044200 [pii]
Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S and Cattaneo E. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science. 2001; 293:493–498. DOI: 10.1126/science.1059581; 1059581 [pii]
Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG, Hersch SM, Mouradian MM, Young AB, Tanese N and Krainc D. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science. 2002; 296:2238–2243. DOI: 10.1126/science.1072613; 1072613 [pii]
Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, Frey AS, Spektor BS, Penney EB, Schilling G, Ross CA, Borchelt DR, Tapscott SJ, Young AB, Cha JH and Olson JM. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum Mol Genet. 2000; 9:1259–1271. DOI: ddd139 [pii]
McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y, Paulson H, Sobue G and Fischbeck KH. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet. 2000; 9:2197–2202.
Cha JH. Transcriptional signatures in Huntington's disease. Prog Neurobiol. 2007; 83:228–248. DOI: S0301-0082(07)00071-8 [pii];10.1016/j.pneurobio.2007.03.004
Arzberger T, Krampfl K, Leimgruber S and Weindl A. Changes of NMDA receptor subunit (NR1, NR2B) and glutamate transporter (GLT1) mRNA expression in Huntington's disease--an in situ hybridization study. J Neuropathol Exp Neurol. 1997; 56:440–454.
Luthi-Carter R, Hanson SA, Strand AD, Bergstrom DA, Chun W, Peters NL, Woods AM, Chan EY, Kooperberg C, Krainc D, Young AB, Tapscott SJ and Olson JM. Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum Mol Genet. 2002; 11:1911–1926.
Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, Sakahira H, Siegers K, Hayer-Hartl M and Hartl FU. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell. 2004; 15:95–105. DOI: 10.1016/j.molcel.2004.06.029; S1097276504003454 [pii]
Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N and Krainc D. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell. 2006; 127:59–69. DOI: 10.1016/j.cell.2006.09.015; S0092-8674(06)01205-0 [pii]
Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D and Cattaneo E. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet. 2003; 35:76–83. DOI: 10.1038/ng1219; ng1219 [pii]
Cong SY, Pepers BA, Evert BO, Rubinsztein DC, Roos RA, van Ommen GJ and Dorsman JC. Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. Mol Cell Neurosci. 2005; 30:560–571.
Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL and Thompson LM. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 2001; 413:739–743. DOI: 10.1038/35099568; 35099568 [pii]
Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PA, Steffan JS, Marsh JL, Thompson LM, Lewis CM, Marks PA and Bates GP. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A. 2003; 100:2041–2046. DOI: 10.1073/pnas.0437870100; 0437870100 [pii]
Thomas EA, Coppola G, Desplats PA, Tang B, Soragni E, Burnett R, Gao F, Fitzgerald KM, Borok JF, Herman D, Geschwind DH and Gottesfeld JM. The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc Natl Acad Sci U S A. 2008; 105:15564–15569. DOI: 10.1073/pnas.0804249105; 0804249105 [pii]
Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, Nieuwland M, Ovaa H, Rottenberg S, van TO, Janssen J, Huijgens P, Zwart W and Neefjes J. Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat Commun. 2013; 4:1908. DOI: 10.1038/ncomms2921; ncomms2921 [pii]
Charbord J, Poydenot P, Bonnefond C, Feyeux M, Casagrande F, Brinon B, Francelle L, Auregan G, Guillermier M, Cailleret M, Viegas P, Nicoleau C, Martinat C, Brouillet E, Cattaneo E, Peschanski M, Lechuga M and Perrier AL. High throughput screening for inhibitors of REST in neural derivatives of human embryonic stem cells reveals a chemical compound that promotes expression of neuronal genes. Stem Cells. 2013; 31:1816–1828. DOI: 10.1002/stem.1430
Conforti P, Zuccato C, Gaudenzi G, Ieraci A, Camnasio S, Buckley NJ, Mutti C, Cotelli F, Contini A and Cattaneo E. Binding of the repressor complex REST-mSIN3b by small molecules restores neuronal gene transcription in Huntington's disease models. J Neurochem. 2013; 127:22–35. DOI: 10.1111/jnc.12348
Silva AJ, Kogan JH, Frankland PW and Kida S. CREB and memory. Annu Rev Neurosci. 1998; 21:127–148. DOI: 10.1146/annurev.neuro.21.1.127
Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR and Goodman RH. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 1993; 365:855–859. DOI: 10.1038/365855a0
Ogryzko VV, Schiltz RL, Russanova V, Howard BH and Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996; 87:953–959. S0092-8674(00)82001-2 [pii]
McCampbell A and Fischbeck KH. Polyglutamine and CBP: fatal attraction? Nat Med. 2001; 7:528–530. DOI: 10.1038/87842; 87842 [pii]
Giralt A, Puigdellivol M, Carreton O, Paoletti P, Valero J, Parra-Damas A, Saura CA, Alberch J and Gines S. Long-term memory deficits in Huntington's disease are associated with reduced CBP histone acetylase activity. Hum Mol Genet. 2012; 21:1203–1216. DOI: 10.1093/hmg/ddr552; ddr552 [pii]
McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS and Fischbeck KH. Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci U S A. 2001; 98:15179–15184. DOI: 10.1073/pnas.261400698; 261400698 [pii]
Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B, Smith K, Kowall NW, Ratan RR, Luthi-Carter R and Hersch SM. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J Neurosci. 2003; 23:9418–9427. DOI: 23/28/9418 [pii]
Jia H, Pallos J, Jacques V, Lau A, Tang B, Cooper A, Syed A, Purcell J, Chen Y, Sharma S, Sangrey GR, Darnell SB, Plasterer H, Sadri-Vakili G, Gottesfeld JM, Thompson LM, Rusche JR, Marsh JL and Thomas EA. Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease. Neurobiol Dis. 2012; 46:351–361.
Jia H, Morris CD, Williams RM, Loring JF and Thomas EA. HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation. Proc Natl Acad Sci U S A. 2015; 112:E56-E64. DOI: 10.1073/pnas.1415195112; 1415195112 [pii]
Moreno CL, Ehrlich ME and Mobbs CV. Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: relation to genes regulating histone acetylation and HTT. Neurobiol Dis. 2016; 85:25–34. DOI: 10.1016/j.nbd.2015.09.012; S0969-9961(15)30058-9 [pii]
Mielcarek M, Landles C, Weiss A, Bradaia A, Seredenina T, Inuabasi L, Osborne GF, Wadel K, Touller C, Butler R, Robertson J, Franklin SA, Smith DL, Park L, Marks PA, Wanker EE, Olson EN, Luthi-Carter R, van der Putten H, Beaumont V and Bates GP. HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biol. 2013; 11:e1001717. DOI: 10.1371/journal.pbio.1001717; PBIOLOGY-D-13-02209 [pii]
Hogarth P, Lovrecic L and Krainc D. Sodium phenylbutyrate in Huntington's disease: a dose-finding study. Mov Disord. 2007; 22:1962–1964. DOI: 10.1002/mds.21632
Butler R and Bates GP. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci. 2006; 7:784–796. DOI: 10.1038/nrn1989; nrn1989 [pii]
Blander G and Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004; 73:417–435. DOI: 10.1146/annurev.biochem.73.011303.073651
Borrell-Pages M, Canals JM, Cordelieres FP, Parker JA, Pineda JR, Grange G, Bryson EA, Guillermier M, Hirsch E, Hantraye P, Cheetham ME, Neri C, Alberch J, Brouillet E, Saudou F and Humbert S. Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest. 2006; 116:1410–1424. DOI: 10.1172/JCI27607
Parker AJ, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H and Neri C. [Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons]. Med Sci (Paris). 2005; 21:556–557. DOI: 10.1051/medsci/2005215556; 00/00/07/5A/[pii]
Kazantsev AG and Hersch SM. Drug targeting of dysregulated transcription in Huntington's disease. Prog Neurobiol. 2007; 83:249–259. DOI: 10.1016/j.pneurobio.2007.02.005; S0301-0082(07)00048-2 [pii]
Minotti G, Menna P, Salvatorelli E, Cairo G and Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004; 56:185–229. DOI: 10.1124/pr.56.2.6;56/2/185 [pii]
Binder DK and Scharfman HE. Brain-derived neurotrophic factor. Growth Factors. 2004; 22:123–131.
Kim HJ, Leeds P and Chuang DM. The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J Neurochem. 2009; 110:1226–1240. DOI: 10.1111/j.1471-4159.2009.06212.x; JNC6212 [pii]
Yasuda S, Liang MH, Marinova Z, Yahyavi A and Chuang DM. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry. 2009; 14:51–59. DOI: 10.1038/sj.mp.4002099; 4002099 [pii]
Dompierre JP, Godin JD, Charrin BC, Cordelieres FP, King SJ, Humbert S and Saudou F. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J Neurosci. 2007; 27:3571–3583. DOI: 10.1523/JNEUROSCI.0037-07.2007; 27/13/3571 [pii]
Rigamonti D, Mutti C, Zuccato C, Cattaneo E and Contini A. Turning REST/NRSF dysfunction in Huntington's disease into a pharmaceutical target. Curr Pharm Des. 2009; 15:3958–3967.
Rigamonti D, Bolognini D, Mutti C, Zuccato C, Tartari M, Sola F, Valenza M, Kazantsev AG and Cattaneo E. Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer element silencer modulators. J Biol Chem. 2007; 282:24554–24562. DOI: 10.1074/jbc.M609885200; M609885200 [pii]
Mansuri ML, Parihar P, Solanki I and Parihar MS. Flavonoids in modulation of cell survival signalling pathways. Genes Nutr. 2014; 9:400. DOI: 10.1007/s12263-014-0400-z
Giralt A, Saavedra A, Carreton O, Xifro X, Alberch J and Perez-Navarro E. Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease. Hum Mol Genet. 2011; 20:4232–4247. DOI: 10.1093/hmg/ddr351; ddr351 [pii]
Manning BD and Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007; 129:1261–1274. DOI: 10.1016/j.cell.2007.06.009; S0092-8674(07)00775-1 [pii]
Saavedra A, Garcia-Martinez JM, Xifro X, Giralt A, Torres-Peraza JF, Canals JM, Diaz-Hernandez M, Lucas JJ, Alberch J and Perez-Navarro E. PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum. Cell Death Differ. 2010; 17:324–335. DOI: 10.1038/cdd.2009.127; cdd2009127 [pii]
Apostol BL, Illes K, Pallos J, Bodai L, Wu J, Strand A, Schweitzer ES, Olson JM, Kazantsev A, Marsh JL and Thompson LM. Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum Mol Genet. 2006; 15:273–285. DOI: 10.1093/hmg/ddi443; ddi443 [pii]
Fan J, Gladding CM, Wang L, Zhang LY, Kaufman AM, Milnerwood AJ and Raymond LA. P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. Neurobiol Dis. 2012; 45:999–1009. DOI: 10.1016/j.nbd.2011.12.019; S0969-9961(11)00394-9 [pii]
Saavedra A, Giralt A, Rue L, Xifro X, Xu J, Ortega Z, Lucas JJ, Lombroso PJ, Alberch J and Perez-Navarro E. Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington's disease: a STEP in the resistance to excitotoxicity. J Neurosci. 2011; 31:8150–8162. DOI: 10.1523/JNEUROSCI.3446-10.2011; 31/22/8150 [pii]
Anglada-Huguet M, Giralt A, Rue L, Alberch J and Xifro X. Loss of striatal 90-kDa ribosomal S6 kinase (Rsk) is a key factor for motor, synaptic and transcription dysfunction in Huntington's disease. Biochim Biophys Acta. 2016; 1862:1255–1266. DOI: 10.1016/j.bbadis.2016.04.002; S0925-4439(16)30073-4 [pii]
Martin E, Betuing S, Pages C, Cambon K, Auregan G, Deglon N, Roze E and Caboche J. Mitogen- and stress-activated protein kinase 1-induced neuroprotection in Huntington's disease: role on chromatin remodeling at the PGC-1-alpha promoter. Hum Mol Genet. 2011; 20:2422–2434. DOI: 10.1093/hmg/ddr148; ddr148 [pii]
Xifro X, Anglada-Huguet M, Rue L, Saavedra A, Perez-Navarro E and Alberch J. Increased 90-kDa ribosomal S6 kinase (Rsk) activity is protective against mutant huntingtin toxicity. Mol Neurodegener. 2011; 6:74. DOI: 10.1186/1750-1326-6-74; 1750-1326-6-74 [pii]
Xifro X, Garcia-Martinez JM, del TD, Alberch J and Perez-Navarro E. Calcineurin is involved in the early activation of NMDA-mediated cell death in mutant huntingtin knock-in striatal cells. J Neurochem. 2008; 105:1596–1612. DOI: 10.1111/j.1471-4159.2008.05252.x; JNC5252 [pii]
Xifro X, Giralt A, Saavedra A, Garcia-Martinez JM, Diaz-Hernandez M, Lucas JJ, Alberch J and Perez-Navarro E. Reduced calcineurin protein levels and activity in exon-1 mouse models of Huntington's disease: role in excitotoxicity. Neurobiol Dis. 2009; 36:461–469. DOI: 10.1016/j.nbd.2009.08.012; S0969-9961(09)00239-3 [pii]
Harper SJ and Wilkie N. MAPKs: new targets for neurodegeneration. Expert Opin Ther Targets. 2003; 7:187–200. DOI: 10.1517/14728184.108.40.206
Maher P, Dargusch R, Bodai L, Gerard PE, Purcell JM and Marsh JL. ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Hum Mol Genet. 2011; 20:261–270. DOI: 10.1093/hmg/ddq460; ddq460 [pii]
Gines S, Ivanova E, Seong IS, Saura CA and MacDonald ME. Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-D-aspartate receptor activation in Huntington's disease knock-in striatal cells. J Biol Chem. 2003; 278:50514–50522. DOI: 10.1074/jbc.M309348200; M309348200 [pii]
Gines S, Paoletti P and Alberch J. Impaired TrkB-mediated ERK1/2 activation in huntington disease knock-in striatal cells involves reduced p52/p46 Shc expression. J Biol Chem. 2010; 285:21537–21548. DOI: 10.1074/jbc.M109.084202; M109.084202 [pii]
Bowles KR and Jones L. Kinase signalling in Huntington's disease. J Huntingtons Dis. 2014; 3:89–123. DOI: 10.3233/JHD-140106; Q576N4V402687284 [pii]
Liebelt B, Papapetrou P, Ali A, Guo M, Ji X, Peng C, Rogers R, Curry A, Jimenez D and Ding Y. Exercise preconditioning reduces neuronal apoptosis in stroke by up-regulating heat shock protein-70 (heat shock protein-72) and extracellular-signal-regulated-kinase 1/2. Neuroscience. 2010; 166:1091–1100. DOI: 10.1016/j.neuroscience.2009.12.067; S0306-4522(09)02157-5 [pii]
Yu CG, Yezierski RP, Joshi A, Raza K, Li Y and Geddes JW. Involvement of ERK2 in traumatic spinal cord injury. J Neurochem. 2010; 113:131–142. DOI: 10.1111/j.1471-4159.2010.06579.x; JNC6579 [pii]
Gokce O, Runne H, Kuhn A and Luthi-Carter R. Short-term striatal gene expression responses to brain-derived neurotrophic factor are dependent on MEK and ERK activation. PLoS One. 2009; 4:e5292. DOI: 10.1371/journal.pone.0005292
Varma H, Cheng R, Voisine C, Hart AC and Stockwell BR. Inhibitors of metabolism rescue cell death in Huntington's disease models. Proc Natl Acad Sci U S A. 2007; 104:14525–14530. DOI: 10.1073/pnas.0704482104; 0704482104 [pii]
Sarantos MR, Papanikolaou T, Ellerby LM and Hughes RE. Pizotifen Activates ERK and Provides Neuroprotection in vitro and in vivo in Models of Huntington's Disease. J Huntingtons Dis. 2012; 1:195–210. DOI: 10.3233/JHD-120033
Maher P, Akaishi T and Abe K. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A. 2006; 103:16568–16573. DOI: 10.1073/pnas.0607822103; 0607822103 [pii]
Scotter EL, Goodfellow CE, Graham ES, Dragunow M and Glass M. Neuroprotective potential of CB1 receptor agonists in an in vitro model of Huntington's disease. Br J Pharmacol. 2010; 160:747–761. DOI: 10.1111/j.1476-5381.2010.00773.x; BPH773 [pii]
Laprairie RB, Bagher AM, Kelly ME and Denovan-Wright EM. Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease. Mol Pharmacol. 2016; 89:364–375. DOI: 10.1124/mol.115.101980; mol.115.101980 [pii]
Pereira A, Zhang B, Malcolm P and Sundram S. Clozapine regulation of p90RSK and c-Fos signaling via the ErbB1-ERK pathway is distinct from olanzapine and haloperidol in mouse cortex and striatum. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 40:353–363. DOI: 10.1016/j.pnpbp.2012.10.025; S0278-5846(12)00281-3 [pii]
Chen RH, Sarnecki C and Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992; 12:915–927.
Deak M, Clifton AD, Lucocq LM and Alessi DR. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38 and may mediate activation of CREB. EMBO J. 1998; 17:4426–4441. DOI: 10.1093/emboj/17.15.4426
Bading H and Greenberg ME. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science. 1991; 253:912–914.
Davis S, Vanhoutte P, Pages C, Caboche J and Laroche S. The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci. 2000; 20:4563–4572. DOI: 20/12/4563 [pii]
De Cesare D, Fimia GM and Sassone-Corsi P. Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends Biochem Sci. 1999; 24:281–285. S0968-0004(99)01414-0 [pii]
Xing J, Ginty DD and Greenberg ME. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science. 1996; 273:959–963.
Xing J, Kornhauser JM, Xia Z, Thiele EA and Greenberg ME. Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol Cell Biol. 1998; 18:1946–1955.
Gonzalez GA, Yamamoto KK, Fischer WH, Karr D, Menzel P, Biggs W, III, Vale WW and Montminy MR. A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence. Nature. 1989; 337:749–752. DOI: 10.1038/337749a0
Parker D, Ferreri K, Nakajima T, LaMorte VJ, Evans R, Koerber SC, Hoeger C and Montminy MR. Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism. Mol Cell Biol. 1996; 16:694–703.
Lonze BE and Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron. 2002; 35:605–623. S0896627302008280 [pii]
Davis GW, Schuster CM and Goodman CS. Genetic dissection of structural and functional components of synaptic plasticity. III. CREB is necessary for presynaptic functional plasticity. Neuron. 1996; 17:669–679. S0896-6273(00)80199-3 [pii]
Walton M, Woodgate AM, Muravlev A, Xu R, During MJ and Dragunow M. CREB phosphorylation promotes nerve cell survival. J Neurochem. 1999; 73:1836–1842.
Bonni A, Brunet A, West AE, Datta SR, Takasu MA and Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 1999; 286:1358–1362.
Zuccato C, Valenza M and Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiol Rev. 2010; 90:905–981. DOI: 10.1152/physrev.00041.2009; 90/3/905 [pii]
Nucifora FC, Jr., Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM and Ross CA. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science. 2001; 291:2423–2428. DOI: 10.1126/science.1056784; 291/5512/2423 [pii]
Ferrer I, Goutan E, Marin C, Rey MJ and Ribalta T. Brain-derived neurotrophic factor in Huntington disease. Brain Res. 2000; 866:257–261. S0006-8993(00)02237-X [pii]
DeMarch Z, Giampa C, Patassini S, Martorana A, Bernardi G and Fusco FR. Beneficial effects of rolipram in a quinolinic acid model of striatal excitotoxicity. Neurobiol Dis. 2007; 25:266–273. DOI: S0969-10.1016/j.nbd.2006.09.006; 9961(06)00236-1 [pii]
Giralt A, Saavedra A, Carreton O, Arumi H, Tyebji S, Alberch J and Perez-Navarro E. PDE10 inhibition increases GluA1 and CREB phosphorylation and improves spatial and recognition memories in a Huntington's disease mouse model. Hippocampus. 2013; 23:684–695. DOI: 10.1002/hipo.22128
Anglada-Huguet M, Vidal-Sancho L, Giralt A, Garcia-Diaz BG, Xifro X and Alberch J. Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity. Neurobiol Dis. 2016; 95:22–34. DOI: 10.1016/j.nbd.2015.09.001; S0969-9961(15)30047-4 [pii]
Miguez A, Garcia-Diaz BG, Brito V, Straccia M, Giralt A, Gines S, Canals JM and Alberch J. Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Hum Mol Genet. 2015; 24:4958–4970. DOI: 10.1093/hmg/ddv218; ddv218 [pii]
Sgambato V, Vanhoutte P, Pages C, Rogard M, Hipskind R, Besson MJ and Caboche J. In vivo expression and regulation of Elk-1, a target of the extracellular-regulated kinase signaling pathway, in the adult rat brain. J Neurosci. 1998; 18:214–226.
Vanhoutte P, Barnier JV, Guibert B, Pages C, Besson MJ, Hipskind RA and Caboche J. Glutamate induces phosphorylation of Elk-1 and CREB, along with c-fos activation, via an extracellular signal-regulated kinase-dependent pathway in brain slices. Mol Cell Biol. 1999; 19:136–146.
Ferrer I, Blanco R and Carmona M. Differential expression of active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38 and specific transcription factor substrates following quinolinic acid excitotoxicity in the rat. Brain Res Mol Brain Res. 2001; 94:48–58. DOI: S0169328X0100198X [pii]
Roze E, Betuing S, Deyts C, Marcon E, Brami-Cherrier K, Pages C, Humbert S, Merienne K and Caboche J. Mitogen- and stress-activated protein kinase-1 deficiency is involved in expanded-huntingtin-induced transcriptional dysregulation and striatal death. FASEB J. 2008; 22:1083–1093. DOI: 10.1096/fj.07-9814; fj.07-9814 [pii]
Anglada-Huguet M, Giralt A, Perez-Navarro E, Alberch J and Xifro X. Activation of Elk-1 participates as a neuroprotective compensatory mechanism in models of Huntington's disease. J Neurochem. 2012; 121:639–648. DOI: 10.1111/j.1471-4159.2012.07711.x
Boros J, O'Donnell A, Donaldson IJ, Kasza A, Zeef L and Sharrocks AD. Overlapping promoter targeting by Elk-1 and other divergent ETS-domain transcription factor family members. Nucleic Acids Res. 2009; 37:7368–7380. DOI: 10.1093/nar/gkp804; gkp804 [pii]
Crosio C, Heitz E, Allis CD, Borrelli E and Sassone-Corsi P. Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons. J Cell Sci. 2003; 116:4905–4914. DOI: 10.1242/jcs.00804; 116/24/4905 [pii]
Cramer H, Warter JM and Renaud B. Analysis of neurotransmitter metabolites and adenosine 3',5'-monophosphate in the CSF of patients with extrapyramidal motor disorders. Adv Neurol. 1984; 40:431–435.
Wyttenbach A, Swartz J, Kita H, Thykjaer T, Carmichael J, Bradley J, Brown R, Maxwell M, Schapira A, Orntoft TF, Kato K and Rubinsztein DC. Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease. Hum Mol Genet. 2001; 10:1829–1845.
Fusco FR and Giampa C. Phosphodiesterases as therapeutic targets for Huntington's disease. Curr Pharm Des. 2015; 21:365–377. DOI: CPD-EPUB-61969 [pii]
Bender AT and Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006; 58:488–520. DOI: 10.1124/pr.58.3.5; 58/3/488 [pii]
Hebb AL, Robertson HA and Denovan-Wright EM. Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington's disease transgenic mice prior to the onset of motor symptoms. Neuroscience. 2004; 123:967–981. S0306452203008418 [pii]
Hu H, McCaw EA, Hebb AL, Gomez GT and Denovan-Wright EM. Mutant huntingtin affects the rate of transcription of striatum-specific isoforms of phosphodiesterase 10A. Eur J Neurosci. 2004; 20:3351–3363. DOI: 10.1111/j.1460-9568.2004.03796.x; EJN3796 [pii]
Giampa C, Laurenti D, Anzilotti S, Bernardi G, Menniti FS and Fusco FR. Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease. PLoS One. 2010; 5:e13417. DOI: 10.1371/journal.pone.0013417
DeMarch Z, Giampa C, Patassini S, Bernardi G and Fusco FR. Beneficial effects of rolipram in the R6/2 mouse model of Huntington's disease. Neurobiol Dis. 2008; 30:375–387. DOI: S0969-9961(08)00040-5 [pii];10.1016/j.nbd.2008.02.010
Giampa C, Middei S, Patassini S, Borreca A, Marullo F, Laurenti D, Bernardi G, Ammassari-Teule M and Fusco FR. Phosphodiesterase type IV inhibition prevents sequestration of CREB binding protein, protects striatal parvalbumin interneurons and rescues motor deficits in the R6/2 mouse model of Huntington's disease. Eur J Neurosci. 2009; 29:902–910. DOI: 10.1111/j.1460-9568.2009.06649.x; EJN6649 [pii]
Ahmad R, Bourgeois S, Postnov A, Schmidt ME, Bormans G, Van LK and Vandenberghe W. PET imaging shows loss of striatal PDE10A in patients with Huntington disease. Neurology. 2014; 82:279–281. DOI: 10.1212/WNL.0000000000000037; WNL.0000000000000037 [pii]
Russell DS, Barret O, Jennings DL, Friedman JH, Tamagnan GD, Thomae D, Alagille D, Morley TJ, Papin C, Papapetropoulos S, Waterhouse RN, Seibyl JP and Marek KL. The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease. JAMA Neurol. 2014; 71:1520–1528. DOI: 10.1001/jamaneurol.2014.1954; 1915581 [pii]
Niccolini F, Haider S, Reis MT, Muhlert N, Tziortzi AC, Searle GE, Natesan S, Piccini P, Kapur S, Rabiner EA, Gunn RN, Tabrizi SJ and Politis M. Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease. Brain. 2015; 138:3016–3029. DOI: 10.1093/brain/awv214; awv214 [pii]
Leuti A, Laurenti D, Giampa C, Montagna E, Dato C, Anzilotti S, Melone MA, Bernardi G and Fusco FR. Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease. Neurobiol Dis. 2013; 52:104–116. DOI: 10.1016/j.nbd.2012.11.016; S0969-9961(12)00379-8 [pii]
Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem. 1987; 56:615–649. DOI: 10.1146/annurev.bi.56.070187.003151
Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF and Babu MM. Molecular signatures of G-protein-coupled receptors. Nature. 2013; 494:185–194. DOI: 10.1038/nature11896; nature11896 [pii]
Brinkmann V and Lynch KR. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr Opin Immunol. 2002; 14:569–575. S0952791502003746 [pii]
Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S and Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 1996; 381:800–803. DOI: 10.1038/381800a0
Kolakowski LF, Jr. GCRDb: a G-protein-coupled receptor database. Receptors Channels. 1994; 2:1–7.
Regan JW. EP2 and EP4 prostanoid receptor signaling. Life Sci. 2003; 74:143–153. S002432050300907X [pii]
Andreasson K. Emerging roles of PGE2 receptors in models of neurological disease. Prostaglandins Other Lipid Mediat. 2010; 91:104–112. DOI: 10.1016/j.prostaglandins.2009.04.003; S1098-8823(09)00021-5 [pii]
Hutchinson AJ, Chou CL, Israel DD, Xu W and Regan JW. Activation of EP2 prostanoid receptors in human glial cell lines stimulates the secretion of BDNF. Neurochem Int. 2009; 54:439–446. DOI: 10.1016/j.neuint.2009.01.018; S0197-0186(09)00034-5 [pii]
Mehta A, Prabhakar M, Kumar P, Deshmukh R and Sharma PL. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur J Pharmacol. 2013; 698:6–18. DOI: 10.1016/j.ejphar.2012.10.032; S0014-2999(12)00900-4 [pii]
Song C, Zhang Y, Parsons CG and Liu YF. Expression of polyglutamine-expanded huntingtin induces tyrosine phosphorylation of N-methyl-D-aspartate receptors. J Biol Chem. 2003; 278:33364–33369. DOI: 10.1074/jbc.M304240200; M304240200 [pii]
Roche KW, Standley S, McCallum J, Dune LC, Ehlers MD and Wenthold RJ. Molecular determinants of NMDA receptor internalization. Nat Neurosci. 2001; 4:794–802. DOI: 10.1038/90498; 90498 [pii]
Li H, Wyman T, Yu ZX, Li SH and Li XJ. Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release. Hum Mol Genet. 2003; 12:2021–2030.
Tang TS, Tu H, Chan EY, Maximov A, Wang Z, Wellington CL, Hayden MR and Bezprozvanny I. Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron. 2003; 39:227–239. S0896627303003660 [pii]
Lievens JC, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le GL and Bates GP. Impaired glutamate uptake in the R6 Huntington's disease transgenic mice. Neurobiol Dis. 2001; 8:807–821. DOI: 10.1006/nbdi.2001.0430; S0969-9961(01)90430-9 [pii]
Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH and Li XJ. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol. 2005; 171:1001–1012. DOI: 10.1083/jcb.200508072; jcb.200508072 [pii]
Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH and Friedlander RM. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000; 6:797–801. DOI: 10.1038/77528
Chen X, Wu J, Lvovskaya S, Herndon E, Supnet C and Bezprozvanny I. Dantrolene is neuroprotective in Huntington's disease transgenic mouse model. Mol Neurodegener. 2011; 6:81. DOI: 10.1186/1750-1326-6-81; 1750-1326-6-81 [pii]
Hansson O, Guatteo E, Mercuri NB, Bernardi G, Li XJ, Castilho RF and Brundin P. Resistance to NMDA toxicity correlates with appearance of nuclear inclusions, behavioural deficits and changes in calcium homeostasis in mice transgenic for exon 1 of the huntington gene. Eur J Neurosci. 2001; 14:1492–1504. DOI: 1767 [pii]
Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, Llinas R, Kristal BS, Hayden MR and Bezprozvanny I. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. Proc Natl Acad Sci U S A. 2005; 102:2602–2607. DOI: 10.1073/pnas.0409402102; 0409402102 [pii]
Kuhn A, Goldstein DR, Hodges A, Strand AD, Sengstag T, Kooperberg C, Becanovic K, Pouladi MA, Sathasivam K, Cha JH, Hannan AJ, Hayden MR, Leavitt BR, Dunnett SB, Ferrante RJ, Albin R, Shelbourne P, Delorenzi M, Augood SJ, Faull RL, Olson JM, Bates GP, Jones L and Luthi-Carter R. Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum Mol Genet. 2007; 16:1845–1861. DOI: 10.1093/hmg/ddm133; ddm133 [pii]
Bezprozvanny I. Calcium signaling and neurodegenerative diseases. Trends Mol Med. 2009; 15:89–100. DOI: 10.1016/j.molmed.2009.01.001; S1471-4914(09)00028-8 [pii]
Saavedra A, Alberch J and Perez-Navarro E, Don’t Take Away My P: Phosphatases as Therapeutic Targets in Huntington’s Disease, Huntington’s Disease - Core Concepts and Current Advances, Dr Nagehan Ersoy Tunali (Ed.), InTech, 2012. DOI: 10.5772/30850. Available from: http://www.intechopen.com/books/huntington-s-disease-core-concepts-and-current-advances/don-t-take-away-my-p-phosphatases-as-therapeutic-targets-in-huntington-s-disease.
Luthi-Carter R, Apostol BL, Dunah AW, DeJohn MM, Farrell LA, Bates GP, Young AB, Standaert DG, Thompson LM and Cha JH. Complex alteration of NMDA receptors in transgenic Huntington's disease mouse brain: analysis of mRNA and protein expression, plasma membrane association, interacting proteins and phosphorylation. Neurobiol Dis. 2003; 14:624–636. S0969996103001724 [pii]
Nithianantharajah J, Barkus C, Murphy M and Hannan AJ. Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington's disease transgenic mice. Neurobiol Dis. 2008; 29:490–504. DOI: 10.1016/j.nbd.2007.11.006; S0969-9961(07)00259-8 [pii]
Giralt A, Rodrigo T, Martin ED, Gonzalez JR, Mila M, Cena V, Dierssen M, Canals JM and Alberch J. Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: involvement of phospholipaseCgamma activity and glutamate receptor expression. Neuroscience. 2009; 158:1234–1250. DOI: 10.1016/j.neuroscience.2008.11.024; S0306-4522(08)01712-0 [pii]
Jarabek BR, Yasuda RP and Wolfe BB. Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model. Brain. 2004; 127:505–516. DOI: 10.1093/brain/awh058; awh058 [pii]
Torres-Peraza JF, Giralt A, Garcia-Martinez JM, Pedrosa E, Canals JM and Alberch J. Disruption of striatal glutamatergic transmission induced by mutant huntingtin involves remodeling of both postsynaptic density and NMDA receptor signaling. Neurobiol Dis. 2008; 29:409–421. DOI: 10.1016/j.nbd.2007.10.003; S0969-9961(07)00237-9 [pii]
Hansson O, Petersen A, Leist M, Nicotera P, Castilho RF and Brundin P. Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. Proc Natl Acad Sci U S A. 1999; 96:8727–8732.
Cepeda C, Ariano MA, Calvert CR, Flores-Hernandez J, Chandler SH, Leavitt BR, Hayden MR and Levine MS. NMDA receptor function in mouse models of Huntington disease. J Neurosci Res. 2001; 66:525–539. DOI: 10.1002/jnr.1244
Hardingham GE and Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. 2010; 11:682–696. DOI: 10.1038/nrn2911; nrn2911 [pii]
Giralt A, Carreton O, Lao-Peregrin C, Martin ED and Alberch J. Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction. Mol Neurodegener. 2011; 6:71. DOI: 10.1186/1750-1326-6-71; 1750-1326-6-71 [pii]
Anglada-Huguet M, Xifro X, Giralt A, Zamora-Moratalla A, Martin ED and Alberch J. Prostaglandin E2 EP1 Receptor Antagonist Improves Motor Deficits and Rescues Memory Decline in R6/1 Mouse Model of Huntington's Disease. Mol Neurobiol. 2013. DOI: 10.1007/s12035-013-8556-x
Berry CT, Sceniak MP, Zhou L and Sabo SL. Developmental up-regulation of vesicular glutamate transporter-1 promotes neocortical presynaptic terminal development. PLoS One. 2012; 7:e50911. DOI: 10.1371/journal.pone.0050911; PONE-D-12-16167 [pii]
Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001; 65:1–105. S0301-0082(00)00067-8 [pii]
Huang K, Kang MH, Askew C, Kang R, Sanders SS, Wan J, Davis NG and Hayden MR. Palmitoylation and function of glial glutamate transporter-1 is reduced in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2010; 40:207–215. DOI: 10.1016/j.nbd.2010.05.027; S0969-9961(10)00189-0 [pii]
Sari Y, Prieto AL, Barton SJ, Miller BR and Rebec GV. Ceftriaxone-induced up-regulation of cortical and striatal GLT1 in the R6/2 model of Huntington's disease. J Biomed Sci. 2010; 17:62. DOI: 10.1186/1423-0127-17-62; 1423-0127-17-62 [pii]
Miller BR, Dorner JL, Shou M, Sari Y, Barton SJ, Sengelaub DR, Kennedy RT and Rebec GV. Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington's disease phenotype in the R6/2 mouse. Neuroscience. 2008; 153:329–337. DOI: 10.1016/j.neuroscience.2008.02.004; S0306-4522(08)00216-9 [pii]
Schiefer J, Landwehrmeyer GB, Luesse HG, Sprunken A, Puls C, Milkereit A, Milkereit E and Kosinski CM. Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease. Mov Disord. 2002; 17:748–757. DOI: 10.1002/mds.10229
Mittal SK and Eddy C. The role of dopamine and glutamate modulation in Huntington disease. Behav Neurol. 2013; 26:255–263. DOI: 10.3233/BEN-2012-120268; F053694311NM83Q4 [pii]
Schilling G, Coonfield ML, Ross CA and Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model. Neurosci Lett. 2001; 315:149–153. S0304394001023266 [pii]
Dau A, Gladding CM, Sepers MD and Raymond LA. Chronic blockade of extrasynaptic NMDA receptors ameliorates synaptic dysfunction and pro-death signaling in Huntington disease transgenic mice. Neurobiol Dis. 2014; 62:533–542. DOI: 10.1016/j.nbd.2013.11.013; S0969-9961(13)00325-2 [pii]
Milnerwood AJ and Raymond LA. Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease. Trends Neurosci. 2010; 33:513–523. DOI: 10.1016/j.tins.2010.08.002; S0166-2236(10)00117-7 [pii]
Dosage effects of riluzole in Huntington's disease: a multicenter placebo-controlled study. Neurology. 2003; 61:1551–1556.
Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Vincent Chen HS, Tong G, Hayden MR and Lipton SA. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med. 2009; 15:1407–1413. DOI: 10.1038/nm.2056; nm.2056 [pii]
Perez-Mato M, Ramos-Cabrer P, Sobrino T, Blanco M, Ruban A, Mirelman D, Menendez P, Castillo J and Campos F. Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia. Cell Death Dis. 2014; 5:e992. DOI: 10.1038/cddis.2013.507; cddis2013507 [pii]
Teichberg VI. GOT to rid the body of excess glutamate. J Cereb Blood Flow Metab. 2011; 31:1376–1377. DOI: 10.1038/jcbfm.2011.46; jcbfm201146 [pii]
Colucci-D'Amato L, Perrone-Capano C and di PU. Chronic activation of ERK and neurodegenerative diseases. Bioessays. 2003; 25:1085–1095. DOI: 10.1002/bies.10355
Biswas SC and Greene LA. Nerve growth factor (NGF) down-regulates the Bcl-2 homology 3 (BH3) domain-only protein Bim and suppresses its proapoptotic activity by phosphorylation. J Biol Chem. 2002; 277:49511–49516. DOI: 10.1074/jbc.M208086200; M208086200 [pii]
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW and Bates GP. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996; 87:493–506. S0092-8674(00)81369-0 [pii]
Endo H, Nito C, Kamada H, Nishi T and Chan PH. Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats. J Cereb Blood Flow Metab. 2006; 26:1479–1489. DOI: 10.1038/sj.jcbfm.9600303; 9600303 [pii]
Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME and Saudou F. The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev Cell. 2002; 2:831–837. S1534580702001880 [pii]
Lievens JC, Iche M, Laval M, Faivre-Sarrailh C and Birman S. AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington's disease. Hum Mol Genet. 2008; 17:882–894. DOI: 10.1093/hmg/ddm360; ddm360 [pii]
Hodges A, Strand AD, Aragaki AK, Kuhn A, Sengstag T, Hughes G, Elliston LA, Hartog C, Goldstein DR, Thu D, Hollingsworth ZR, Collin F, Synek B, Holmans PA, Young AB, Wexler NS, Delorenzi M, Kooperberg C, Augood SJ, Faull RL, Olson JM, Jones L and Luthi-Carter R. Regional and cellular gene expression changes in human Huntington's disease brain. Hum Mol Genet. 2006; 15:965–977. DOI: 10.1093/hmg/ddl013; ddl013 [pii]
Fitzpatrick CJ and Lombroso PJ. The role of striatal-enriched protein tyrosine phosphatase (STEP) in cognition. Front Neuroanat. 2011; 5:47. DOI: 10.3389/fnana.2011.00047
Braithwaite SP, Paul S, Nairn AC and Lombroso PJ. Synaptic plasticity: one STEP at a time. Trends Neurosci. 2006; 29:452–458. DOI: S0166-10.1016/j.tins.2006.06.007; 2236(06)00121-4 [pii]
Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ and Raymond LA. Calpain and STriatal-Enriched protein tyrosine phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model. Hum Mol Genet. 2012; 21:3739–3752. DOI: 10.1093/hmg/dds154; dds154 [pii]
Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P, Ghosh D, Kanyo J, Zhang Y, Seyb K, Ononenyi C, Foscue E anderson GM, Gresack J, Cuny GD, Glicksman MA, Greengard P, Lam TT, Tautz L, Nairn AC, Ellman JA and Lombroso PJ. Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease. PLoS Biol. 2014; 12:e1001923. DOI: 10.1371/journal.pbio.1001923; PBIOLOGY-D-14-00425 [pii]
Kaminska B, Gaweda-Walerych K and Zawadzka M. Molecular mechanisms of neuroprotective action of immunosuppressants--facts and hypotheses. J Cell Mol Med. 2004; 8:45–58. DOI: 008.001.05 [pii]
Rusnak F and Mertz P. Calcineurin: form and function. Physiol Rev. 2000; 80:1483–1521.
Malleret G, Haditsch U, Genoux D, Jones MW, Bliss TV, Vanhoose AM, Weitlauf C, Kandel ER, Winder DG and Mansuy IM. Inducible and reversible enhancement of learning, memory and long-term potentiation by genetic inhibition of calcineurin. Cell. 2001; 104:675–686. S0092-8674(01)00264-1 [pii]
Asai A, Qiu J, Narita Y, Chi S, Saito N, Shinoura N, Hamada H, Kuchino Y and Kirino T. High level calcineurin activity predisposes neuronal cells to apoptosis. J Biol Chem. 1999; 274:34450–34458.
Almeida S, Domingues A, Rodrigues L, Oliveira CR and Rego AC. FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures. Neurobiol Dis. 2004; 17:435–444. DOI: 10.1016/j.nbd.2004.07.002; S0969-9961(04)00151-2 [pii]
Metzler M, Gan L, Mazarei G, Graham RK, Liu L, Bissada N, Lu G, Leavitt BR and Hayden MR. Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A. J Neurosci. 2010; 30:14318–14329. DOI: 10.1523/JNEUROSCI.1589-10.2010; 30/43/14318 [pii]
Pineda JR, Pardo R, Zala D, Yu H, Humbert S and Saudou F. Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease. Mol Brain. 2009; 2:33. DOI: 10.1186/1756-6606-2-33; 1756-6606-2-33 [pii]
Hernandez-Espinosa D and Morton AJ. Calcineurin inhibitors cause an acceleration of the neurological phenotype in a mouse transgenic for the human Huntington's disease mutation. Brain Res Bull. 2006; 69:669–679. DOI: 10.1016/j.brainresbull.2006.03.013; S0361-9230(06)00112-2 [pii]
Chiu CT, Liu G, Leeds P and Chuang DM. Combined treatment with the mood stabilizers lithium and valproate produces multiple beneficial effects in transgenic mouse models of Huntington's disease. Neuropsychopharmacology. 2011; 36:2406–2421. DOI: 10.1038/npp.2011.128; npp2011128 [pii]
Gardian G, Browne SE, Choi DK, Klivenyi P, Gregorio J, Kubilus JK, Ryu H, Langley B, Ratan RR, Ferrante RJ and Beal MF. Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease. J Biol Chem. 2005; 280:556–563. DOI: 10.1074/jbc.M410210200; M410210200 [pii]
Mielcarek M, Benn CL, Franklin SA, Smith DL, Woodman B, Marks PA and Bates GP. SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington's disease. PLoS One. 2011; 6:e27746. DOI: 10.1371/journal.pone.0027746; PONE-D-11-16241 [pii]
Jia H, Wang Y, Morris CD, Jacques V, Gottesfeld JM, Rusche JR and Thomas EA. The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntington's Disease Mice. PLoS One. 2016; 11:e0152498. DOI: 10.1371/journal.pone.0152498; PONE-D-15-53149 [pii]
Hathorn T, Snyder-Keller A and Messer A. Nicotinamide improves motor deficits and upregulates PGC-1alpha and BDNF gene expression in a mouse model of Huntington's disease. Neurobiol Dis. 2011; 41:43–50. DOI: 10.1016/j.nbd.2010.08.017; S0969-9961(10)00276-7 [pii]
Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR and Raymond LA. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron. 2002; 33:849–860. S0896627302006153 [pii]
Gratuze M, Noel A, Julien C, Cisbani G, Milot-Rousseau P, Morin F, Dickler M, Goupil C, Bezeau F, Poitras I, Bissonnette S, Whittington RA, Hebert SS, Cicchetti F, Parker JA, Samadi P and Planel E. Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease. Hum Mol Genet. 2015; 24:86–99. DOI: 10.1093/hmg/ddu456; ddu456 [pii]
Graham RK, Pouladi MA, Joshi P, Lu G, Deng Y, Wu NP, Figueroa BE, Metzler M andre VM, Slow EJ, Raymond L, Friedlander R, Levine MS, Leavitt BR and Hayden MR. Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease. J Neurosci. 2009; 29:2193–2204. DOI: 10.1523/JNEUROSCI.5473-08.2009; 29/7/2193 [pii]
Strong MK, Southwell AL, Yonan JM, Hayden MR, Macgregor GR, Thompson LM and Steward O. Age-dependent resistance to excitotoxicity in Htt CAG140 mice and the effect of strain background. J Huntingtons Dis. 2012; 1:221–241. DOI: 10.3233/JHD-129005