It is well defined that subpopulations of motoneurons have different vulnerability to the pathology causing amyotrophic lateral sclerosis (ALS). In the spinal cord, the fast fatigable motoneurons have been shown to be the first to degenerate, followed by fatigue-resistant and slow motoneurons. In contrast motoneurons located in the Onuf’s and oculomotor nuclei appear to be resistant to disease. With a focus on research mainly done on mice overexpressing the mutated human superoxide dismutase (SOD1) protein, we review recent studies exploring the mechanisms that underlie the selective vulnerability of the various motoneuron subtypes. By comparing differences in gene expression between these populations, it has been possible to identify factors, which critically determine the survival of motoneurons and the neuromuscular function in the pathologic context of ALS. Furthermore, we discuss the contribution of non-cell autonomous processes, involving glial cells and the skeletal muscle, in the neurodegenerative process. Exploring the cause of neurodegeneration from the angle of the selective neuronal vulnerability has recently led to the identification of novel targets, which open opportunities for therapeutic intervention against ALS.
- selective vulnerability
- therapeutic target
- ER stress
Amyotrophic lateral sclerosis (ALS) primarily affects the motor system, which controls both voluntary and involuntary movements, including vital functions such as breathing, through the activity of various types of motoneurons (MNs). Paralysis and death of the patients, which typically occurs within a few years after disease onset, is caused by the progressive dysfunction and degeneration of MNs in the cortex, brainstem and spinal cord. Remarkably, it has been established that the different types of MNs are not equally affected by ALS. This leads to contrasted effects on the motor system. For instance, with disease progression, patients lose their ability to speak, swallow and move, but they keep normal visual, sexual and bladder functions. Indeed, MNs located in the oculomotor and Onuf’s nuclei are remarkably resistant to the disease . In contrast, spinal MNs controlling voluntary movements, hypoglossal MNs important for swallowing and breathing, as well as the upper MNs, are typically among the first neurons to degenerate.
Upper MNs, also known as Betz cells or corticospinal MNs (CSMNs), are glutamatergic neurons located in the primary motor cortex and which activate lower MNs in the brainstem and spinal cord. Upon activation, the lower MNs induce muscle contraction via the release of the acetylcholine neurotransmitter in the neuromuscular junction (NMJ), a specialized synapse contacting the skeletal muscle fibers. The ensemble formed by lower MNs and the innervated muscle fiber is called the motor unit.
Spinal MNs are subdivided into α, β and γ MNs, depending on the type of muscle fibers they innervate (reviewed by ). In ALS, it is mainly α-MNs that degenerate. However, it is recognized that within the class of α-MNs, there is also a predictable variation in neuronal vulnerability to disease [3, 4]. It is therefore important to distinguish the following subtypes of α-MNs, defined by the contractile properties of the motor unit they are part of: the fast twitch fatigable (FF) MNs, the fast twitch fatigue-resistant (FR) MNs and the slow twitch fatigue-resistant (S) MNs . This classification is also based on other characteristics, such as the size of the neuronal soma (FF MNs have larger cell bodies than S MNs), axonal conduction velocity (FF MNs are faster than S MNs), dendrite branching (FF MNs display a more complex dendritic tree than S MNs) , as well as the electrical properties of each of these MN subtypes .
The selective vulnerability observed between the different types of MNs provides a remarkable opportunity to explore the factors that specifically contribute to neurodegeneration. Until now, this approach has been mainly based on animal models overexpressing mutated forms of the superoxide dismutase 1 (SOD1) protein. Indeed, in more than 20% of the familial ALS cases (fALS), the SOD1 protein carries point mutations associated with autosomal dominant inheritance. Rodent models overexpressing mutated forms of SOD1 (mSOD1), often under the control of the human SOD1 promoter, faithfully replicate major clinical aspects of ALS [8–10]. Furthermore, MN subpopulations display a selective vulnerability pattern very similar to the one observed in humans . These animal models are therefore instrumental to investigate the molecular and cellular mechanisms underlying the disease process. In this review, we will discuss how the research on ALS has identified novel therapeutic targets by comparing different MN subtypes in SOD1 models of fALS.
2. Comparing different populations of MNs
A careful analysis of disease progression in the high-copy SOD1G93A mouse models of ALS has allowed defining different stages of the disease. The first behavioral alterations occur as early as postnatal day 10 (P10), with a delay in the righting reflex and an increase in the number of mistakes observed in forelimb placement . Around P50, subtle changes in mouse gait and muscle strength can be observed [12, 13] and by P80, clear impairments in the motor performance can be detected . At 3 months of age, the animals reach disease onset, which is characterized by fine tremors, muscle atrophy and loss of body mass . A severe paralysis of the hindlimbs is observed on average at P120 . Soon after P135, the ALS mice become unable to right themselves when placed on their side, which is considered as the humane disease endpoint . This highly reproducible course of the disease has been used to identify the corresponding neurodegenerative events in the mouse spinal cord. Thorough analysis has revealed a precise sequence in the loss of the different types of MNs, allowing for longitudinal studies to determine molecular and cellular correlates in the disease process.
2.1. Progression of the SOD1 pathology in mouse models of fALS
2.1.1. Spinal MNs
Spinal MNs are responsible for the control of voluntary movements. For instance, MNs located in the lumbar part of the spinal cord control the movement of the hindlimbs (Figure 1). These MNs innervate muscles, such as the
A significant decline of the compound muscle action potential (CMAP) is observed around P50 [17, 18], followed by a second decline seen around P100 [18, 19]. In line with the CMAP data, histological analysis has revealed an abrupt loss of muscle innervation at the age of approximately 50 days, corresponding to lower occupation of the NMJ in the fast twitch muscle [3, 14]. Therefore, SOD1 pathology leads first to a loss of the innervation of the type IIb muscle fibers by the FF MNs (Figure 2B). The second wave of denervation, which occurs at the late presymptomatic stage of the disease, is defined by the pruning of the FR axons innervating the type IIa muscle fibers  (Figure 2C). In contrast, the type I muscle fibers remain innervated by the S MNs almost until end stage . Moreover, FR and S MNs have been shown to have a higher capacity for axonal sprouting compared to the FF MNs . They may form new synapses on the denervated end plates  (Figure 2B, C). Although the loss of NMJs is typically observed early during the course of the pathology induced by mSOD1, the degeneration of MN cell bodies in the ventral horn starts at P100 and rapidly progresses, in line with the “dying back” process described by .
Overall, these studies highlight a predictable course of degeneration in the SOD1 mouse model, with evident differences in the vulnerability of the different subtypes of spinal MN. Whereas FF MNs are more sensitive to the pathology than FR MNs, the S MNs appear remarkably resistant to the disease. Saxena
2.1.2. Corticospinal MNs
The CSMNs localized in the layer V of the motor cortex are responsible for the initiation of the voluntary movement. These glutamatergic neurons collect, integrate, translate and transmit signals to lower MNs located in the spinal cord (Figure 1). CSMNs degenerate and die in ALS patients [21, 22]. There is also experimental evidence for the degeneration of CSMNs in the SOD1 animal models of fALS . However, their role in the SOD1G93A mouse model has been long overlooked; as without specific markers, it was difficult to discriminate these cells from other types of pyramidal neurons located in the layer V of the cortex. Retrograde tracers, as well as some adeno-associated viral (AAV) vectors able to retrogradely transduce neurons from their axonal projections, have proved their utility to study CSMNs . Using retrograde tracers, a degeneration of the corticospinal tract and a loss of CSMNs were observed at end stage in SOD1G93A fALS mice . By combining retrograde tracers together with morphological and molecular approaches, Ozdinler
However, it remains unclear what is the exact contribution of CSMN degeneration to the deficits observed in animal models of the SOD1 fALS pathology. Importantly, the silencing of mSOD1 in the cortex of SOD1G93A rats can delay disease onset, and extends animal survival . Even more, the treatment has neuroprotective effects on spinal MNs, preventing denervation of the NMJs. These data highlight the role of CSMNs in ALS, which may have been underestimated. Further longitudinal studies will be needed to explore the molecular mechanisms leading to CSMN degeneration in ALS and uncover potential therapeutic targets.
2.2. Transversal studies to compare motor nuclei
2.2.1. Onuf/oculomotor versus spinal/hypoglossal MNs
Pools of MNs located in the Onuf’s and oculomotor nuclei are considered resistant to the disease. MNs located in the oculomotor nucleus are responsible for most of the eye movements. This function remains mostly intact in ALS patients, although slight defects can be detected toward end stage, in patients maintained with respiratory assist devices (reviewed by ). Similarly, the disease does not affect the survival of MNs in the Onuf’s nucleus, which controls sexual and bladder functions . In this nucleus, only few degenerating hallmarks have been observed, such as pyknotic nuclei or Bunina bodies . The apparent resistance of the oculomotor and Onuf’s nuclei contrasts with the progressive degeneration of spinal, hypoglossal and trigeminal MNs responsible for the locomotion, swallowing and the control of the jaw musculature, respectively [33, 34] (Figure 1).
Several research groups have taken advantage of the differential vulnerability between these motor nuclei to investigate the underlying molecular mechanisms [35–37]. These studies used techniques including the local injection of retrograde tracers, laser microdissection of cell subtypes and high-throughput analysis of gene expression.
Using microarrays, Kaplan
Another study compared oculomotor MNs, hypoglossal MNs and cervical spinal MNs in WT rats, and found that the pattern of expression of a set of genes was specific for each of these MN subpopulations . Based on those results, protein levels were determined for six key genes, comparing their expression in WT and SOD1G93A mice . This study identified a protein expression signature specific to the disease-resistant oculomotor MNs, as compared to hypoglossal and spinal MNs. The GABAA receptor α1, the guanylate cyclase soluble subunit α3 and the parvalbumin protein were highly expressed in the resistant MNs. Conversely, vulnerable MNs displayed higher protein levels of dynein, peripherin and GABAA receptor α2. These data suggest that differences in excitability, calcium handling and retrograde transport machinery may underlie the observed vulnerability pattern. Remarkably, these differences in protein expression were found to be conserved in the mouse and human species .
In an electrophysiological study using the high-copy SOD1G93A mouse model, Venugopal
Overall, despite the fact that these different pools of MNs have similar physiological roles, they display clear differences in their vulnerability to the ALS pathology. Transversal studies have already identified some of the mechanisms that may confer MN susceptibility to the disease.
3. Possible mechanisms implicated in selective motoneuron vulnerability
Here, we will summarize both intrinsic and extrinsic mechanisms, which may underlie the differences between subtypes of MNs in their ability to cope with the ALS pathology.
3.1. Intrinsic mechanisms
3.1.1. SOD1 misfolding and ER chaperones
One of the leading hypotheses for the cause of ALS is the gain of toxic properties resulting from the accumulation of misfolded proteins including SOD1. In normal conditions, the cytosolic SOD1 protein undergoes several maturation steps to acquire proper structure and function. These steps include the binding of copper and zinc and the formation of an intramolecular disulfide bond, to form an enzymatically active and stable homodimer . When the SOD1 protein carries pathogenic mutations, it has an increased propensity to misfold (misfSOD1), leading to aggregation and accumulation in organelles such as the Endoplasmic Reticulum (ER) and the mitochondria . Aggregation of SOD1 has been observed in patients with fALS [44, 45] and has also been reported in sporadic cases of ALS (sALS) [45, 46]. Using antibodies that specifically recognize misfSOD1 , Saxena
In-depth analysis showed that two ER chaperones have an important role in MN vulnerability: Calreticulin (CRT) and SIL1 (Figure 2D). CRT is a protein that binds Ca2+ ions. Interestingly CRT has been shown to be two-fold decreased in the FF MNs compared to S MNs, as soon as P38 .
In an effort to find factors regulating the ER stress response in specific pools of MNs, Filézac de l’Etang
By comparing cranial and spinal MNs with the disease-resistant oculomotor and Onuf’s nuclei in WT mice, the MMP-9 protein was found to be expressed only in the vulnerable MNs . MMPs are zinc-dependent endopeptidases able to degrade extracellular matrix and basement membrane components. Although the role of MMP-9 in the context of ALS is still poorly understood, it might be involved in the disruption of the neuronal extracellular matrix interaction (reviewed by ). MMPs have also been shown to promote the inflammatory process . Kaplan
Although no mutations in MMP-9 gene have been linked to ALS yet, He
3.1.3. Neuronal excitability
FF and S MNs also differ in their excitability profile. Because of their small soma size, the S MNs have high input resistance, and therefore need less synaptic activation to initiate an action potential. As compared to MNs with a larger soma size, the firing threshold is reached earlier in S MNs, followed by the FR and finally the FF MNs . S MNs are therefore considered to be highly excitable, whereas FF MNs are poorly excitable. S MNs innervate slow twitch muscle fibers, which are typically part of the postural muscles, whereas the poorly excitable neurons control fast twitch fibers, highly present in phasic muscles, and which are used when strength or rapid response is needed. A recent study by Saxena
Recently, a study further explored the link between misfSOD1 accumulation and MN excitability. Ruegsegger
3.2. Extrinsic mechanisms
3.2.1. CNS compartment
Over the 20 past years, it has been long debated whether ALS should be considered as a cell autonomous disease, mainly taking place in the MNs. It is now well established that astrocytes, oligodendrocytes and microglia also play a role in the pathology (reviewed by [58, 59]). Animal models of the SOD1 pathology have been intensively used to address this question. First, when the mSOD1 was selectively expressed in neurons using a panneuronal promoter, an ALS phenotype was observed only after 400 days . It was next observed that expression of mSOD1 with a MN-specific promoter does not produce any ALS phenotype [61, 62]. Similarly, expression of mSOD1 only in astrocytes or microglia failed to produce any pathology [63, 64]. Next, several studies used fALS mice carrying a floxed mSOD1 transgene to selectively excise the transgene by expressing the Cre recombinase only in a given cell types. Using this approach, they could demonstrate that mSOD1 expression in MNs determines the time of disease onset. Expression of mSOD1 in either astrocytes or oligodendrocytes affects both disease onset and progression [65, 66], whereas the pathogenic contribution of mSOD1 in microglial cells is mainly observed during disease progression . Similar effects have been observed with a different approach, using an AAV-based system to selectively express an artificial microRNA to target mSOD1 either in MNs or in astrocytes .
The majority of the vulnerable MNs are already degenerating before the clinical onset of the disease (Figure 2). When the resistant pool of MNs undergoes degenerative changes, they are typically exposed to a local environment containing reactive glial cells. Indeed, astrocytes and microglia become activated mainly in the late phase of the pathology. Several studies have shown their implication in the progression of the disease after the onset of the symptoms, most likely via their pathogenic interaction with the remaining MNs.
These findings point out the importance to investigate the role of broad range of cell types in the ALS pathology. Sun
Oligodendrocytes are known to support the metabolic activity and the myelination of axons in the CNS (reviewed by ). Degenerating oligodendrocytes have been observed in ALS mice and patient tissues. Moreover, the pool of oligodendrocyte progenitors, identified by the expression of NG2, fails to properly differentiate, and they generate oligodendrocytes lacking expression of the myelin basic protein (MBP) and monocarboxylate transporter 1 (MCT1) [65, 72]. The loss of MCT1 may contribute to MN vulnerability, as this transporter is normally required for the supply of lactate, which is an important energy substrate for axonal support . Remarkably, MCT4—another lactate transporter— is preferentially expressed in astrocytes and is reduced in ALS .
Although the role of astrocytes in ALS has raised a lot of interest, the mechanisms underlying astrocyte-mediated toxicity toward MNs are still incompletely resolved. The interaction between astrocytes and MNs has been mainly explored
Therefore, although glial cells are essential to support the function and metabolism of MNs in the healthy CNS, they are likely to play an active role in the disease process. Astrocytes, oligodendrocytes and microglial cells carrying ALS-causing mutations appear to malfunction, leading to the selective death of MNs.
The release of misfSOD1 is another major component, which may contribute to MN degeneration via extrinsic mechanisms. As mentioned before, misfSOD1 plays an important role in the degeneration of MNs and its toxicity has been implicated in many cellular dysfunctions (review by ). Most importantly, recent evidence suggests a role of misfSOD1 also in some sALS cases that are not related to SOD1 mutations. It has been demonstrated that misfSOD1 can convert WT SOD1 [84, 85] leading to the formation of fibrils and aggregates
Although experimental evidence for the propagation of misfSOD1 is still lacking
3.2.2. PNS compartment
On top of the CNS components, it is also important to investigate the role of cells that may control the function of specific subtypes of MNs in the periphery, especially the Schwann cells and the skeletal muscle.
126.96.36.199. Schwann cells
The Schwann cells are the counterparts of oligodendrocytes in the peripheral nervous system (PNS), as they are the primary supporting and myelinating cells for the neurons in the PNS. Surprisingly, the suppression of mSOD1 in Schwann cells accelerates disease progression . The terminal Schwann cells (TSCs) are also of particular interest as they play an important role in the maintenance, plasticity and regeneration of the NMJs (reviewed by ). Semaphorin 3A (Sema3a), a chemorepellent expressed by TSC, is involved in the repulsion of motor axons away from the end plate, leading to the denervation of the NMJ . Remarkably, during reinnervation or toxin-induced paralysis of the
One of the first changes observed in ALS patients and mouse models is the denervation of the NMJ, often long before the death of MNs. However, the role of the muscle in ALS is still debated (reviewed by ). Dobrowolny
4. Identification and validation of therapeutic targets
Despite years of research and clinical testing, Riluzole remains the only FDA approved drug for ALS. It is therefore urgent to identify novel targets for therapeutic intervention against MN degeneration. The study of the different types of MNs highlights the fact that subpopulations of MNs can survive for long term and function in the context of the disease, which provides novel molecular targets for neuroprotective treatments.
One possibility is to identify factors that are active in the most vulnerable neurons, and design approaches to reduce their activity, with the hope to obtain neuroprotective effects in ALS. In SOD1 mice, MMP-9 has recently been shown to cause deleterious effects in the FF MNs, where it is preferentially expressed . Edaravone is a free radical scavenger that inhibits MMP-9 upregulation . This compound has been used since many years ago for the treatment of cerebral infarction or ischemic stroke. Edaravone has demonstrated therapeutic efficiency in the SOD1G93A mouse model  as well as in the SOD1H46R rat model , and more recently in the wobbler mice, which is often considered as a model for sALS . A phase II clinical trial has shown that Edaravone can slow down the progression of the motor impairments in ALS patients, although this effect could not be statistically confirmed in a recent phase III trial . Nevertheless, further analysis of the results has revealed the beneficial effects of the compound in a subgroup of ALS patients, according to the revised El Escorial diagnostic criteria, prompting the initiation of a new trial (http://www.alzforum.org/news/conference-coverage/does-free-radical-scavenger-edavarone-slow-als).(http://www.alzforum.org/news/conference-coverage/does-free-radical-scavenger-edavarone-slow-als). Of note, Edaravone is already approved in Japan for the treatment of ALS.
Another possibility is to identify proteins that are expressed only in the disease-resistant MNs. Here, factors implicated in the control of ER stress may play an important role in MNs (reviewed by ). Possible therapeutic approaches to relieve ER stress have been tested in the context of the ALS mice. For instance, Salubrinal has been shown to reduce ER stress . In SOD1 mice, Salubrinal administration alleviates disease manifestation and slows down the progression of the disease . However, Salubrinal as such cannot be used for treating ALS patients as it has been shown to affect long-term memory in mice . Guanabenz is another FDA approved antihypertensive drug known to reduce ER stress. Its efficacy in ALS mice is however still controversial [117, 118]. It is therefore important to unravel targets that may be more specific to ALS. The discovery that the ER chaperones SIL1 and CRT are centrally involved in the most resistant populations of MNs has raised attention to these factors as potential specific targets [49, 50]. In particular, AAV-mediated overexpression of SIL1 in the MNs of ALS mice dramatically increases innervation of the NMJs and prolongs animal survival by 25—30%. However, it remains to be determined how to therapeutically target these factors in ALS patients, perhaps using adapted pharmacological approaches.
As the vulnerability of MNs could be caused by the accumulation of misfSOD1 in these cells, one potential therapeutic strategy is to prevent SOD1 toxicity by targeting the partially unfolded intermediates of the SOD1 protein that can later form aggregates. Israelson
Another approach to prevent SOD1 misfolding is to provide the metal cofactors that are critical for the proper folding and stability of the functional Cu/Zn SOD1 dimer (reviewed by [119, 120]). CuATSM is a chelator widely used for PET-imaging as it rapidly carries copper across the blood-brain barrier into the CNS. Preclinical studies in SOD1 mouse models have reported beneficial effects of CuATSM, including on animal survival [121, 122]. Recently, Williams
Other strategies directly target SOD1 to prevent its deleterious effects. The use of antibodies specific for misfSOD1 has been proposed [47, 124, 125]. On the other hand, gene therapy techniques can be used to reduce the overall level of SOD1 expression. This approach can be considered as SOD1 null mice are viable and do not show any obvious motor dysfunction (reviewed by ). Viral vectors delivering artificial shRNA or microRNA for RNA interference against SOD1 [68, 127–130], as well as antisense oligonucleotides targeting the SOD1 mRNA , are currently being investigated to suppress the expression of this protein. It remains however debated whether these techniques could be effective in patients other than those carrying SOD1 mutations, as the role of SOD1 in sALS remains unclear . Nevertheless, some mechanisms contributing to SOD1 toxicity, such as ER stress and UPR, are likely to be implicated in a broad range of ALS cases, providing opportunities for largely applicable treatments.
5. Selective neuronal vulnerability in non-SOD1 ALS and other motoneuron diseases
Most of the studies described in this chapter have used the SOD1 mouse model to explore the selective vulnerability of MNs in ALS . The pattern on MN vulnerability in ALS patients is still a matter of speculation. At the late stage of the disease, there is a dramatic degeneration of the MNs throughout the spinal cord. However, as the access to
It is also likely that differences exist between familial and sALS, as well as between the different genetic forms of ALS. This may also reduce the efficacy of therapies tested in the SOD1 model. SOD1 mutations are the cause of ALS only in a small fraction of the patients. In addition, the SOD1 pathology does not appear to be associated with Frontotemporal-Lobar degeneration, which is linked with other forms of ALS (FTLD-ALS) . Therefore, there is an urgent need for other models of ALS to develop therapies better adapted to the different forms of the disease. During the past 10 years, genetic studies have identified ALS-causing mutations in several genes mainly involved in RNA metabolism, such as FUS, TARDBP and C9ORF72. FUS and TARDBP represent around 3 and 5% of fALS, respectively, whereas C9ORF72 cases are more prevalent and cover 30—50% of fALS as well as 5—7% of sALS . Moreover, these genes have been found mutated in both ALS and FTLD-ALS patients, and TDP-43 positive inclusions are observed in non-SOD1 ALS patients . Several research groups have generated rodents either overexpressing mutated forms of these genes or carrying gene deletions, with the objective to model the ALS pathology. Overall, the current rodent models for TDP-43-ALS or FUS-ALS display relatively mild MN degeneration. Axonal degeneration has been seen in the transgenic TDP-43 rat model, which seems to selectively affect the largest MNs . This observation suggests that selective vulnerability is also likely to occur in the TDP-43 pathology.
Recently, more emphasis has been placed on modeling C9ORF72-ALS. Mouse lines generated with a bacterial artificial chromosome carrying a pathogenic hexanucleotide expansion in the full human C9ORF72 gene did not develop any behavioral symptoms in two independent studies [136, 137]. By contrast, using AAV vectors to express the G4C2 repeat expansion in the mouse CNS led to both histological and behavioral defects similar to the pathology observed in C9ORF72-ALS/FTLD patients . Although 20% of neuron death was measured in the cortex, motor cortex and cerebellum of these mice, the number of spinal cord MNs was not reported. With the continuous development of ALS models, it will hopefully be possible to more accurately design therapeutic approaches against pathogenic pathways that may be common to different forms of ALS.
The recent development of mouse and human ES and iPS cells could provide an alternative to
Lately, the transcriptome of the cerebellum and frontal cortex was analyzed
More generally, it is tempting to speculate that the selective MN vulnerability observed in ALS may also apply to other MN disorders, such as spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) diseases. In SMA patients, muscle biopsies show atrophy of the type II muscle fibers, with a compensatory hypertrophy of the type I fibers . Moreover, the Onuf’s nucleus is preserved, even in the most severely affected SMA type I patients. Even though atrophy is restricted to certain muscles in mouse models of the disease, it does not seem to be related to muscle fiber type or NMJ size . However, the large size MNs innervating the proximal forelimb and axial muscles are specifically lost in presymptomatic Δ7 SMN mice . This last observation could indicate a preferential vulnerability of some MN subtypes, although this will need to be confirmed with more specific markers to identify the FF or S MNs.
CMT is a heterogeneous group of genetic diseases affecting motor and/or sensory functions. Several genes have been identified linked to demyelinating CMT (CMT1) or axonal CMT (CMT2). Among the CMT2 cases, 20% are caused by mutations in the MFN2 gene encoding mitofusin 2 and are referred as CMT2A . Several observations indicate a pattern of neurodegeneration, which may be very different from ALS. Biopsies of the
The identification of ALS-causing mutations in the SOD1 gene in 1993 has raised hopes in the ALS scientific community . One year later, Gurney
Nevertheless, the characterization of mouse models overexpressing mutant forms of SOD1 has dramatically improved our understanding of the cellular processes leading to ALS. In particular, the very reproducible course of the disease observed in these mice has been instrumental to study the different stages of the disease, highlighting the fact that not all MNs are equally affected, and that glial cells are important actors in the pathogenic process. Recently, several research groups have identified critical factors, which determine MN vulnerability, providing novel targets for therapeutic intervention. One obvious difficulty in designing treatments for ALS is that at a given stage of the disease, the various pools of MNs or glial cells may face different toxic mechanisms, depending on their intrinsic vulnerability. This may limit the therapeutic efficacy of a single drug.
It remains unknown whether the observed MN vulnerability pattern is specific to mSOD1, and if the identified molecular mechanisms can be applied to other forms of ALS. To address this question, it is critical to further develop animal and cellular models of ALS, based on the genes, which have recently been linked to the disease. By comparing these models, it will be possible to pinpoint common pathogenic pathways, and with the development of more specific biomarkers, apply therapies when and where they are the most likely to succeed.
This work was supported by the Swiss National Science Foundation (Grant 310030L_156460) and by ERANET E-Rare FaSMALS (Grant 31ER30_160673). NBM is supported by the Neuromuscular Research Association Basel (NeRAB).
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