1. Introduction
Protein and organelle turnover is essential to maintain cellular homeostasis and survival. Removing and recycling cell constituents is achieved by autophagy in all cells, including neurons. Autophagy contributes to various physiological processes, such as intracellular cleansing, cellular homeostasis, development, differentiation, longevity, tumor suppression, elimination of invading pathogens, antigen transport to the innate and adaptative immune systems, and counteracting endoplasmic reticulum (ER) stress and diseases characterized by the accumulation of protein aggregates [1]. Autophagy plays a role in a number of infectious and inflammatory diseases, in addition to protein unfolding and misfolding diseases that lead to neuron, muscle and liver degeneration or heart failure [2-4]. Whereas autophagy has long been defined as a form of non-apoptotic, programmed cell death [5], recent findings suggest that autophagy functions primarily to sustain cells, and only defects in autophagy lead to cell death [6].
2. Autophagy in neuronal physiology
Autophagy was initially identified and characterized in a few cell types including neurons. The distinct vacuoles which feature this self-eating process were originally described at the ultrastructural level [7, 8]. The formation of autophagosomes was associated with chromatolysis of a restricted neuroplasm area, free of organelles, but filled with various types of vesicles [9]. The function of autophagy in mature neurons , however, is still debated. In comparison with other organs, rodent brains show high expression levels of autophagy-related (Atg) proteins and low levels of autophagy markers such as autophagosome number and LC3-II. Indeed, even under prolonged fasting conditions, the number of autophagosomes does not increase in neurons, probably because their nutrient supply from peripheral organs is maintained [10]. However, mice with CNS defects in their autophagic machinery exhibit neurological deficits, such as abnormal limb-clasping reflexes, locomotor ataxia, and lack of motor coordination, in addition to a significant loss of large pyramidal neurons in the cerebral cortex and Purkinje cells (PCs) in the cerebellar cortex [11-13].
Macroautophagy (hereafter referred to as autophagy) is initiated when a portion of the cytoplasm is sequestrated within a double-membrane organelle, the so-called autophagosome [14]. The autophagic machinery has been extensively detailed at the molecular level in a number of reviews including several chapters of this book [14-17]. Atg and several non-Atg proteins have been identified as regulators of key steps leading to the degradation of cytosolic components in lysosomes: initiation and nucleation of phagophores, expansion of autophagosomes, maturation of autophagosomes into amphisomes/autolysosomes, and execution of autophagic degradation [18]. The endosomal sorting complex required for transport (ESCRT) pathway functions in the sorting of transmembrane proteins into the inner vesicles of multivesicular bodies (MVB) during endocytosis. Also it is conceivably an essential part of the basal autophagy process in neurons because ubiquitin- or p62/SQSTM1 (p62)-labelled inclusions and autophagosomes accumulate in neurons deficient in ESCRT components [19]. Increasing evidence suggests that autophagy is regulated in a cell type-specific manner and as such autophagy may serve a distinct function in neurons and may show difference in the molecular machinery underlying basal autophagy (Fig. 1).
2.1. Axonal autophagy
In neurons, autophagy occurs in axons, suggesting that it may be uniquely regulated in this compartment and specifically adapted to local axonal physiology [20]. In primary dorsal root ganglion neurons, autophagosomes initiate distally in nerve terminals and mature during their transport toward the cell soma [21, 22]. In non-neuronal cells, the autophagosomal membrane has multiple possible origins, including endocytosed plasma membrane (amphisome), ER, mitochondria, and trans-Golgi membranes [18, 21, 23- 32]. In contrast, the origin of autophagosomes in the axons is likely to be restricted to the sources of membrane available in the terminals such as smooth ER and plasma membrane [33, 34], excluding rough ER and Golgi dictyosomes.
As observed in ultrastructural studies of axotomized neurons [9, 35], analysis of Purkinje cell (PC) degeneration in lurcher mutant GluRδ2Lc [36] demonstrates autophagosomes in their axonal compartment. In this study, an excitotoxic insult mediated by GluRδ2Lc triggered a rapid and robust accumulation of autophagosomes in dystrophic axonal swellings providing evidence that autophagy is induced in dystrophic terminals and that autophagosome biogenesis occurs in axons [37]. The molecular scenario underlying the initiation of this axonal autophagy is unclear. Liang
2.2. Microtubule-dependent dynamics of neuronal autophagy
Previous data indicate that autophagy is a microtubule-dependent process. In cultured sympathetic neurons, autophagosomes formed in the distal ends of axon undergo retrograde transport along microtubules to the cell body where lysosomes that are necessary for the degradation step of autophagy are usually located [21]. Consistent with these observations, prominent retrograde transport of GFP-LC3-labelled autophagosomes has been observed in the axons of primary cerebellar granule cells [36]. In serum-deprived PC12 cells, autolysosomes formed by fusion of autophagosomes with lysosomes move in both anterograde and retrograde directions in neurites, and this trafficking requires microtubules [41]. Furthermore, both pharmacological and siRNA-based inhibition of directional microtubule motor proteins kinesin and dynein partially block respectively, anterograde and retrograde neuritic transport of autophagosomes, indicating that they participate in this transport. Recent observations in primary dorsal root ganglionic neurons support a maturation model in which autophagosomes initiate distally, engulfing mitochondria and ubiquitinated cargo, and move bidirectionally along microtubules driven by bound anterograde kinesin and retrograde dynein motors [22]. Fusion with late endosomes or lysosomes may then allow autophagosomes to escape from the early distal pool by robust retrograde dynein-driven motility. The involvement of the dynein-dynactin complex in the movement of autophagosomes along microtubules to lysosomes has also been demonstrated in non-neuronal cells [42]. Consistent with the formation of an autolysosomal compartment, autophagosomes increasingly acidify as they approach the cell soma, thereby fueling the catalysis of the degradation of their engulfed contents. Fully acidified autolysosomes undergo bidirectional motility suggesting reactivation of kinesin motors [22, 41].
The interaction of the autophagic membrane marker Atg8/LC3 with the microtubule-associated protein 1B (MAP1B) [43] implicates microtubule-dependent, axon-specific regulation of autophagosomes. Overexpression of MAP1B in non-neuronal cells reduces the number of LC3-associated autophagosomes without impairing autophagic degradation. The scarcity of LC3-labelled autophagosomes in CNS neurons under normal conditions may be explained by their high expression levels of MAP1B [10, 36]. By modifying microtubule function, the LC3-MAP1B interaction has been proposed to accelerate the delivery of LC3-autophagosomes to lysosomes, thereby promoting efficient autophagic turnover [37]. The exact mechanism underlying the involvement of microtubule in autophagosome formation, as well as targeting and fusion with lysosomes is open to debate [44, 45]. Based on (
2.3. Functions of neuronal autophagy
Neurons, as non-dividing cells, are more sensitive to toxic components than dividing cells. Therefore, their survival and the maintenance of their specialized functions under physiological and pathological conditions is crucial requiring a tight quality control of cytoplasmic components and their degradation. Autophagy is believed to be of particular importance in the synaptic compartments of neurons where high energy requirements and protein turnover are necessary to sustain synaptic growth and activity. The CNS displays relatively low levels of autophagosomes under normal conditions, even after starvation, but requires an indispensable turnover of cytosolic contents by autophagy even in the absence of any disease-associated mutant proteins [10, 47, 48]. The scarcity of immature autophagosomes in neurons is likely to reflect a highly efficient autophagic degradation in the healthy brain. Accordingly, inhibition of autophagy causes neurodegeneration in mature neurons suggesting that autophagy may regulate neuronal homeostasis [11, 12]. For example, abnormal protein accumulation and eventual neurodegeneration are observed in the CNS of mice lacking the
2.3.1. Axonal homeostasis
Constitutive autophagy is probably essential for axonal homeostasis. Suppression of basal autophagy by either deleting an
Indeed, dysfunctional autophagy has been implicated in axonal dystrophy. Axonal swellings occur in autophagy-deficient mouse brains [11, 12] and genetic ablation of
2.3.2. Dendritic autophagy
Early autophagosomes have also been observed in dendrites and the cell body of neurons suggesting that axon terminals are not be the only sites where neuronal autophagosomes form, and that autophagy may play a regulatory function in dendrites under physiological and pathological conditions [19]. Along this line, mTOR a key regulator of the autophagic pathway, modulates postsynaptic long-term potentiation and depression, suggesting that autophagy may critically control synaptic plasticity at the postsynaptic, dendritic compartment [61]. Further investigations are required to determine the specific roles of autophagy in dendrites and axons.
Since autophagosomes can fuse with endosomes and form amphisomes, there is a link between autophagy and endocytosis [62]. ESCRT proteins have recently been implicated in normal autophagy [19, 63, 64]. The endocytic pathways, in particular multi-vesicular bodies (MVBs) may serve as critical routes for autophagosomes to reach lysosomes, because defects in ESCRT function prevents fusion or maturation of autophagosomes. The ESCRT-MVB pathway could represent the primary, if not the only, route for delivering autophagosomes to lysosomes in some cell types [20]. In neurons, a large part of the endocytosed cargo merges with the autophagic pathway prior to being degraded by lysosomes [65]. Alterations in ESCRT function have also been linked to autophagy-deficiency in fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In these cases, the particular vulnerability of the neurons appears to be associated with a dysfunction in the autophagosome-MVB pathway in the dendritic compartment [19].
2.3.3. Protein homeostasis
Neurons deficient in Atg5 or Atg7 exhibit an accumulation of polyubiquitinated proteins in inclusion bodies even though the proteasome function is normal, suggesting that basal autophagy prevents spontaneous protein aggregation and plays an essential role in protein clearance and homeostasis in neurons. Such a function is even more critical in neurons expressing disease-related proteins like the aggregate-prone mutant α-synuclein and polyglutamine-containing proteins [66-68], although how autophagy selectively degrades these disease-related proteins is unclear. The ubiquitin-associated protein p62 is a likely candidate, providing a link between autophagy and selective protein degradation. Indeed, p62 binds numerous proteins through multiple protein-protein interacting motifs, including one for LC3 [55, 56] and the ubiquitin-associated C-terminal domain which binds ubiquitinated proteins. The relationship between p62 and autophagy is further supported by the observation that a marked accumulation of p62 and LC3 occurs only when lysosomes, but not proteasomes, are blocked. Furthermore, p62 protein levels are elevated in autophagy-deficient neurons [36, 55]. This argues that p62 is a specific substrate of autophagic degradation rather than a molecule involved in autophagosome formation since p62-knockout mice display intact autophagosomes and slower protein degradation. Autophagy-deficient cells and neurons accumulate ubiquitin- and p62-positive inclusions, and this accumulation is greatly reduced by ablating p62 [55, 69]. p62 with mutations in the LC3 recognition sequence escape autophagic degradation, leading to the formation of inclusions, whereas those with mutations in the self-oligomerizing domain PB1 are poorly degraded, but no protein inclusions form. Thus increased levels and oligomerization of p62 are required for the formation of inclusion bodies, and their degradation is facilitated by oligomerization. Ubiquitinated aggregates induced by proteasome inhibition are also reduced in p62-deficient cells suggesting that p62 is a general mediator of inclusion formation and normally functions as an adaptator targeting proteins for autophagic degradation [20].
2.3.4. Neuronal autophagy in synapse development, function and remodeling
Neuronal autophagy has been recently shown to play an important role in synapse development. The ubiquitin-proteasome system negatively regulates growth of the neuromuscular junction (NMJ) in
Autophagy has recently been shown to regulate neurotransmission at the presynaptic level [76]. Besides enhancing protein synthesis via the mTORC1 complex, mTOR activity inhibits autophagy by an Atg13 phosphorylation-induced blockade of Atg1 [77]. In the nervous system, mTORC1 promotes learning and synaptic plasticity dependent on protein synthesis [78- 80]. Conversely, the mTOR inhibitor rapamycin impedes protein synthesis and blocks cell injury-induced axonal hyperexcitability and synaptic plasticity, as well as learning and memory [81, 82]. In prejunctional dopaminergic axons, inhibition of mTOR induces autophagy as shown by an increase in autophagosome formation, and decreases axonal volume, synaptic vesicle number and evoked dopamine release. Similarly, non-dopaminergic striatal terminals also display more autophagosomes and fewer synaptic vesicles. Conversely, chronic autophagy deficiency in dopamine neurons increases dopaminergic axon size and evoked dopamine release, and promotes rapid presynaptic recovery. Thus mTOR-dependent axonal autophagy locally regulates presynaptic structure and function. In cultured brain slices, the occurrence of autophagosomes in presynaptic terminals isolated from their cell bodies confirms that autophagosomes are locally synthesized [83], and supports the view that this autophagy may serve to modulate presynaptic terminal function by sequestrating presynaptic components [76]. The global stimulating effect of chronic autophagy deficiency on dopaminergic neurons is consistent with the implication of autophagy in neurite retraction of sympathetic neurons
There are only a few other reports indicating that autophagy may participate in synapse remodeling. In the cerebellar cortex of the (
2.4. Few autophagosomes, a feature of basal neuronal autophagy
Neurons are highly resistant to large-scale induction of autophagy in response to starvation, probably due to the multiple energy sources available to assure their function [48]. Interestingly, the activity of mTOR, a negative regulator of autophagy is significantly reduced in hypothalamic neurons from mice after a 48h starvation [91], although there are reports that autophagy in neurons can be regulated independently of mTOR [92, 93]. For example, insulin impairs the induction of neuronal autophagy
Neurons may depend less on autophagy to provide free amino acids and energy under physiological conditions given their quasi exclusive use of blood-born glucose as a source of carbon and energy for protein synthesis. Accordingly, the primary function of neuronal autophagy may be different than a primary response to starvation, and autophagy regulatory mechanisms are likely to be specific in neurons. Furthermore, gender differences in autophagic capacity have been suggested by the faster autophagic response to starvation of cultured neurons from male rats compared to those from females [94]. While
3. Autophagy in neuronal physiopathology
Autophagy normally protects effect against neurodegeneration, but defects in the autophagy machinery are sufficient to induce neurodegeneration. Indeed, neuron-specific disruption of autophagy results in neurodegeneration [11, 12]; for example PC-specific Atg7 deficiency impedes axonal autophagy via an important p62-independent axonopathic mechanism associated with neurodegeneration [55]. Furthermore, specific defects in selective autophagic components or in the cargo selection process can induce neurodegeneration. This hypothesis is supported by the studies of cargo recognition and degradation components, such as p62, NBR1, or ALFY [109, 110]. Defects at any one of the autophagic steps can cause an abnormal accumulation of cytosolic components and lead to disease states. Therefore, each step of the autophagic process needs to be tightly regulated for efficient autophagic degradation.
The housekeeping role of neuronal autophagy is more evident when neurons are loaded with pathogenic proteins [67]. In many neurodegenerative disorders, cytoplasmic, nuclear and extracellular inclusions composed of aggregated and ubiquitinated proteins are believed to contribute to organelle damage, synaptic dysfunction and neuronal degeneration. The autophagic process in diseased neurons participates in the clearance of abnormal aggregate-prone proteins such as the expanded glutamine (polyQ)-containing proteins (e.g. mutant huntingtin in Huntington’s disease (HD)), mutant forms of α-synuclein in familial Parkinson disease (PD), different forms of tau in Alzheimer’s disease (AD), tauopathies and FTD, mutant forms of SOD1 in motor diseases such as ALS, and mutant forms of PMP22 in peripheral neuropathies are cleared from diseased neurons by autophagy [19, 20, 55, 56, 66, 67, 111-115]. However, accumulation of these intracellular aggregates is believed to play a significant role in the etiology of neurodegenerative diseases including prion diseases (PrD) [3, 67]. One common feature is the dramatic cyto-pathological accumulation of autophagosomes in injured and degenerating neurons [116-121]. Such signs of defects in autophagy have been interpreted as a result of an “autophagic stress”, or in other words an imbalance between protein synthesis and degradation [116]. This has traditionally been viewed as a highly destructive cellular mechanism, driving the cell to death [117]. In these diseases, it is now accepted that autophagy eliminates aggregate-prone proteins and damaged organelles more efficiently than the proteasome machinery. Since the proteasome is unable to degrade them [122], the clearance of misfolded, aggregated proteins originating from neuropathologic deficits is highly dependent on autophagy. However, a blockade of the autophagic flux is likely to impede the clearance of these proteins. The accumulation of aggregated proteins and organelles within the diseased neurons then contributes to cell dysfunction and in the end results in cell death [16], (Fig. 3). Indeed, pharmacological upregulation of autophagy reduces neuronal aggregates and slows down the progression of neurological symptoms in animal models of tauopathy and HD [123], AD [41, 124, 125] and PrD [126, 127].
The mechanisms that determine the activation of autophagy for the removal of aggregated proteins are not clearly understood, but failure of the other proteolytic systems to handle the altered proteins seems to at least partly underlie autophagy activation. Thus oligomers and fibers of particular proteins can block the proteolytic activity of the ubiquitin-proteasome system and chaperone-mediated autophagy (CMA) that results in autophagy upregulation [128, 129]. In addition, sequestration of negative regulators of autophagy in the protein aggregates could also provoke activation of this pathway. Thus it has been shown that blockage of autophagy in neurons leads to the accumulation of aggregated proteins and neurodegeneration even in the absence of aggregate-prone proteins [11, 12]. Although the specific reasons for the failure of the proteolytic systems are unknown, factors such as enhanced oxidative stress and aging seem to precipitate entry into a late failure stage when the activity of all degradation systems are blocked or decreased, leading to accumulation of autophagic vacuoles and aggregates and finally cell death [130].
Autophagy protects against cell death in the case of growth factor withdrawal, starvation and neurodegeneration, but it is required for some types of autophagic cell death [131-134]. However, the role of autophagy as a positive mediator of cell death is not well understood in mammalian systems, although many studies suggest that impaired autophagy sensitizes cells and organisms to toxic insults. Atg1-dependent autophagy restricts cell growth [135]. Cells deficient in Pdk1, a positive regulator of mTOR pathway [136], display autophagy and reduced growth. The increased growth capacity that results from disrupting autophagy may contribute to the tumorigenicity of cells mutant for tumor suppressors [38, 137, 138]. Overexpression of Atg1 leads to apoptotic cell death [135]. Cells undergoing autophagic cell death display signs of apoptosis [139], as do Atg1-null cells [135]. Thus, elevated levels of autophagy promote cell death and the role of autophagy in cell death is likely to be context-dependent.
Neuronal autophagy is currently believed to constitute a protective mechanism that slows the advance of neurodegenerative disorders, and that its inhibition is associated with neurodegeneration [130]. Substantial attention is currently being focused on the molecular mechanisms underlying the autophagic fight against neurodegeneration, the role of autophagy in early stages of pathogenesis and therapeutical approaches to upregulate protective neuronal autophagy. It is unclear whether accumulation of autophagic vacuoles in degenerating neurons results from increased autophagic flux or impaired flux. A chronic imbalance between autophagosome formation and degradation causes “autophagic stress” [140]. Due to obvious therapeutic consequences, it is imperative to understand how autophagic stress occurs in each autophagy-associated neurodegenerative condition: either a cellular incapacity to support an excessive autophagic demand or a defective degradation (lysosomal) step [141].
4. Autophagy in prion diseases
4.1. Prion diseases
4.1.1. Infectious and familial prion diseases
Prion diseases (PrD) are transmissible spongiform encephalopathies (TSEs) which are fatal neurodegenerative diseases in humans (Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), variant CJD (vCJD), fatal familial insomnia (FFI) and kuru) and in animals (bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME), chronic wasting disease (CWD) and scrapie). In humans, PrD manifest after a long incubation period free of symptoms as a rapid progressive dementia that leads inevitably to death. Severe loss of neurons with extensive astrogliosis and moderate microglial activation, characteristic of all TSEs, results in a progressive spongiform degeneration of the brain tissue which is reflected by ataxia, behavioral changes and, in humans, a progressive cognitive decline [142-145]. According to the protein-only hypothesis [146], TSEs are caused by prions that are believed to be proteinaceous infectious particles mainly consisting of PrPSC, an abnormal isoform of the normal, host-encoded prion protein (PrPC), [142]. Prions are able to catalyze a switch from PrPC conformation into an aggregated misfolded conformer PrPSC which collects throughout the brain according to a prion strain-specific anatomo-pathologic signature. These PrDs share a protein misfolding feature with other neurodegenerative diseases (e.g. AD, PD and HD), [147].
The central role played by PrPC in the development of PrD was first illustrated by the observation that disruption of the PrP gene (PRNP) in mice confers resistance to PrD and impairs the propagation of infectious prions [148], while PrP-overexpressing (
4.1.2. Autophagy in prion-infected neurons
Prion propagation involves the endocytic pathway, specifically the endosomal and lysosomal compartments that are implicated in trafficking and recycling, as well as the final degradation of prions. Shifting the equilibrium between propagation and lysosomal clearance impairs the cellular prion load. This and the presence of autophagic vacuoles in prion diseased neurons [173, 174] suggest a role for autophagy in prion infection (reviewed in [172]). Indeed, the high numbers of autophagic vacuoles observed in neurons from experimentally prion-infected mice (Fig. 4A, B,
Fig. 5) and hamsters is indicative of a robust activation of autophagy [175, 176]. Furthermore, autophagic vacuoles and multivesicular bodies have been detected in prion-infected neuronal cells in vitro [177].The formation of autophagic vacuoles has recently been observed in neuronal pericarya, neurites and synapses of neurons experimentally infected with scrapie, CJD and GSS [174], as well as in neuronal synaptic compartments in humans with certain PrD [173]. PrDs are further correlated with autophagy given that the Scrg1 protein (encoded by the scrapie responsive gene1,
The role of lysosomes in PrDs is still controversial. Although autophagic lysosomal degradation of PrPSC in infected neurons is supposed to clear prion aggregates and inhibit PrPSC replication, there are indications that PrPSC may subvert the autophagic-lysosomal system to promote the conversion of PrPC into PrPSC. Lysosomal inhibitors prevent the build-up of PrPSC [126] and agonists of the autophagy-lysosome pathway enhance the clearance of PrPSC [185, 186, 126]. However, as PrPSC production increases, the accumulating PrPSC may saturate the clearance capacity of the system causing lysosomal disruption and release of PrPSC aggregates into the neuroplasm. In turn this would cause cell stress and over-activate autophagy, as has been reported in prion-diseased brain tissue [183].
The octapeptide repeats region of PrPC has been shown to negatively influence autophagy. As measured by LC3-II expression, autophagy induced by serum deprivation occurs earlier and to a greater extent in hippocampal neurons from ZH-I
Whether autophagy-inducing compounds are candidates for therapeutic approaches against prion infection has recently been investigated in prion-infected mice. Starting in the last third of the incubation periods, treatment with rapamycin and to a lesser extent with lithium significantly prolonged incubation times compared to mock-treated control mice [126, 172]. Along this line, activation of the class III histone deacetylase Sirtuin 1 (Sirt1) has been shown to mediate the neuroprotective effect of resveratrol against prion toxicity [199] and prevent prion protein-derived peptide 106-126 (PrP106-126) neurotoxicity via autophagy processing [200]. Moreover, Sirt1-induced autophagy protects against mitochondrial dysfunction induced by PrP106-126, whereas siRNA knockdown of Sirt1 sensitizes cells to PrP106-126-induced cell death and mitochondrial dysfunction. Finally, knockdown of Atg5 decreases LC3-II protein levels and blocks the effect of a Sirt1 activator against PrP106-126-induced mitochondrial dysfunction and neurotoxicity. Thus inducing Sirt1-mediated autophagy may be a principal neuroprotective mechanism against prion-induced mitochondrial apoptosis. Nevertheless, understanding the mechanisms underlying Sirt1-mediated autophagy against prion neurotoxicity and mitochondrial damage merits further investigation, in particular determining the Sirt1-mediated dowstream signaling network, including FOXOs, p53 and PGC-1α. More recently, the mTOR inhibitor and autophagy inducer rapamycin has been shown to delay disease onset and prevent PrP plaque deposition in a mouse model of the Gerstmann-Sträussler-Scheinker PrD [127]. Here, the reduction in symtom severity and prolonged survival correlate with increases in LC3-II levels in the brains of treated mice, suggesting that autophagy induction enhances elimination of misfolded PrP before plaques form. This is in agreement with the well known neuroprotective effects of rapamycin in various models of neurodegenerative diseases with misfolded aggregate-prone proteins (e.g. PD [111], ALS [201], HD [115], spinocerebellar ataxia [66, 202], FTD [203] and AD [41, 124, 125].
4.2. Doppel-expressing prion protein-deficient mice
Research efforts to determine the function of PrPC using knockout mutant mice have revealed that large deletions in the PrPC genome result in the ectopic neuronal expression of the prion-like protein Doppel (Dpl) causing late onset degeneration of PCs and ataxia in
Similar PC degeneration is observed when the N-terminal truncated form of PrP is expressed (ΔPrP) in
4.2.1. Autophagy in prion protein-deficient mice
The Dpl-activated, BAX-independent cell death mechanism may involve neuronal autophagy as we have detected the expression of Scrg1, a novel protein with a potential link to autophagy in the Ngsk
To further investigate the neurodegenerative mechanisms induced by Dpl in Ngsk cerebellar PCs, we are using an organotypic cerebellar culture system which allows an easier way to approach mechanistic questions than in vivo models [236]. For this purpose, we have assessed the growth and viability of PCs in cerebellar organotypic cultures from Ngsk and ZH-I
Our results have shown that PrPC has a neuroprotective role in cerebellar PCs. As PCs survive
Furthermore, autophagy is more enhanced in
4.2.2. Prion protein PrP-doppel Dpl chimeras
When overexpressed ectopically in neurons, mutations within the central region of PrPC are associated with severe neurotoxic activity, similar to that of Dpl [231, 243]. The absence of these segments, called central domains (CD) is believed to be responsible for neurodegeneration and ataxia. To understand the dual neurotoxicity
5. Perspectives
The beneficial effects that autophagy has on prion infections is currently supported by a growing bulk of evidence from
Overall, the results point to a need to counteract cell stress and to eliminate toxic aggregate-prone proteins that eventually saturate the usual degradation pathways, including autophagy. These are common features of prion disesase and most of the other neurodegenerative diseases described in this review. Saturation of the autophagic machinery, loss or imbalance of autophagic flux is believed to lead to neurodegeneration. Understanding how autophagy relates to these diseases is a first step for developing autophagy modulation-based therapies for treating neurological disorders. This implies therapeutic consideration for each type of autophagic default at a precise step of the neurodegenerative disease concerned.
Acknowledgments
The authors are greatly indebted to Dr. Anne-Marie Haeberlé (CNRS UPR3212, Strasbourg) for excellent assistance in transmission electron microscopy and prion-infected tissue handling as well as to Dr. Catherine Vidal (Institut Pasteur, Paris) for intra-cerebellar inoculation of mice with 22L scrapie. A. R. is supported by a doctoral grant from the French Minister of Research and Technology and A. G. is supported by a grant from the French Centre National de la Recherche Scientifique and the AgroParisTech High School.
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