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Deciphering genetic interactions between ALS genes using C. elegans Martine Therrien a
ab
& J Alex Parker
abc
CRCHUM; Montréal, QC Canada
b
Departement de pathologie et biologie cellulaire; Universite de Montréal; Montréal, QC Canada c
Departement de neurosciences; Universite de Montréal; Montréal, QC Canada Published online: 08 May 2014.
Click for updates To cite this article: Martine Therrien & J Alex Parker (2014) Deciphering genetic interactions between ALS genes using C. elegans, Worm, 3:2, e29047, DOI: 10.4161/worm.29047 To link to this article: http://dx.doi.org/10.4161/worm.29047
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Worm 3, e29047; April 2014; © 2014 Landes Bioscience
Deciphering genetic interactions between ALS genes using C. elegans Martine Therrien1,2 and J Alex Parker1,2,3* CRCHUM; Montréal, QC Canada; 2Departement de pathologie et biologie cellulaire; Universite de Montréal; Montréal, QC Canada; Departement de neurosciences; Universite de Montréal; Montréal, QC Canada
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Keywords: ALS, C9ORF72, FUS, PGRN, SOD1, TDP-43, neurodegeneration *Correspondence to: J Alex Parker; Email: [email protected] Submitted: 03/05/2014 Revised: 04/14/2014 Accepted: 04/28/2014 http://dx.doi.org/10.4161/worm.29047
myotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder causing selective death of motor neurons in which it is speculated that 10% of cases have a familial history. In the past 20 years, many genes causative for ALS have been discovered, but the link between them and their roles in neurodegeneration remain unknown. The identification of genes associated with both ALS and frontotemporal dementia (FTD), along with the observation of patients affected by both diseases, have suggested that they are part of the same neurodegenerative spectrum. Investigating possible genetic interactions among ALS/FTD genes could help understand the role of these genes in neurodegeneration. To pursue this goal, our group has developed several ALS models to study potential genetic interactions. More recently, we characterized the deletion mutant alfa-1, the ortholog of C9ORF72, to evaluate the potential genetic interactions between C9ORF72/ alfa-1 and other ALS genes. Here, we discuss the genetic interactions identified in our models and how some of these proteins may also be linked to other neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing selective motor neuron loss. The disease usually starts in the lower limbs, spreading upwards causing death within 3 to 5 y after the onset of symptoms.1,2 Most cases of ALS are sporadic, but it is speculated that 10% are familial.3 Familial and sporadic ALS cases are clinically indistinguishable, thus identifying disease pathogenesis in familial cases would help understand the pathogenesis of sporadic ALS cases. High-throughput
sequencing technologies have been used to great success over the past few years to identify genetic components of ALS. This has led to the rapid identification of more than 20 genes linked to ALS.3 Among the major ALS genes are Superoxide Dismutase 1 (SOD1),4 TAR DNA Binding Protein (TARDBP),5,6 Fused in Sarcoma (FUS),7 and C9ORF72.8,9 The identification of TDP-43, SOD1, OPTN, FUS, UBQLN2, and NEFH in most aggregates seen in ALS patient tissues suggests that these proteins are involved in disease pathogenesis.10 Many hypotheses11-13 have been put forth regarding the different toxic pathways leading to neurodegeneration; however, no consensus has been reached. Perhaps, more importantly, there are no drugs that effectively slow or halt neuronal loss in ALS patients. An unfortunate recurring theme is that many drugs that were promising candidates in preclinical trials using rodent models have failed in humans.14 Many of these compounds focused on mechanisms to reduce protein aggregation or neuronal death, but recent hypotheses suggest that drugs targeting early pathogenic events could be more effective. However, since ALS diagnosis is difficult and disease progression is rapid, the identification of biological markers is essential for effective therapeutic intervention.
Genetic Interaction Among ALS Genes Many genes linked to ALS appear to have common cellular function. For example, RNA metabolism is a recurrent theme with TDP-43, FUS,
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Figure 1. An emerging genetic network for neurodegeneration. A genetic network of genes underlying neurodegeneration demonstrating the central role of genes linked to the ALS-FTD disease spectrum. Tractable genetic systems like C. elegans are essential to investigate this genetic network of neuronal degeneration. Listed are human proteins linked to disease along with their C. elegans ortholog in parentheses. Abbreviations: ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; FUS, fused in sarcoma; MAPT, microtubule associated protein tau; PGRN, progranulin; SOD1, superoxide dismutase 1; UBQLN2, ubiquilin 2.
HNRNPA2B1, SETX, HNRNPA1, and ARHGEF28 all being involved in this pathway.3 A better understanding of the normal biological roles and the specific pathways affected by mutations may shed light on pathogenic mechanisms in the disease state. Work toward this goal has been done to identify protein–protein interaction networks and protein–RNA interactions of ALS proteins. However, proteins like TDP-43 and FUS have numerous roles affecting the metabolism of thousands of RNAs.12 Also, cells have many compensating pathways, so the genes involved in ALS might not all function in the same pathway, or interact directly but rather be in pathways that have similar functions. Thus, a genetic network of ALS genes would be an essential tool to the understanding of ALS pathogenesis. Finding the relation between ALS genes could be done through the analysis of possible genetic interactions. Genetic interactions are not always easy to determine, but if genes interact it may mean they function in the same pathway or in a compensating cellular pathway.15 To study genetic pathways, model organisms are essential. Analyzing genetic interactions requires models that can
be easily genetically modified and in which phenotypes can be quickly and easily observed. An increasingly popular model with these characteristics is the nematode Caenorhabditis elegans. Our laboratory aims, with the use of different C. elegans models, to unravel some of the interactions in this putative ALS genetic network. To do so, we have developed several C. elegans models to study ALS. The expression of the mutant TDP-43A315T or FUSS57Δ proteins in the animal’s GABAergic motor neurons results in age-dependent motility defects, neurodegeneration, and increased endoplasmic reticulum (ER) stress,16,17 recapitulating important features of ALS pathogenesis. The loss-of-function mutant of tdp1, the C. elegans ortholog of TDP-43, decrease the toxicity observed in these transgenic animals, suggesting an interaction between TDP-1 and TDP-43 and TDP-1 and FUS.17 Unpublished results using fust-1, the worm ortholog of FUS, deletion mutant, also suggest that it participates in mutant TDP-43 and mutant FUS proteotoxicity. Using these models we have determined that TDP-1/TDP43 and FUST-1/FUS genetically interact and modify the progression of motor neuron degeneration. In a recent publication, we aimed to model the toxicity of C9ORF72. In patients, a pathogenic GGGGCC repeat was identified in the first intron of C9ORF72.8,18 The function of C9ORF72 is not fully known but a recent study suggests it has roles in endosomal trafficking.19 However, it is still unclear if the mutation results in a loss of function, a gain of function, or both.20 In patients, hypermethylation of the pathoghenic GGGGCC repeat was shown to decrease the expression of C9ORF72.18,21,22 To model the decreased expression of C9ORF72, we examined the C. elegans ortholog alfa-1 (ALS/FTD associated gene homolog) and a mutation harboring a deletion of the third and fourth exons of the gene leading to a drastic reduction in gene expression. Mutant alfa-1 worms exhibited motility defects leading to an age-dependent paralysis and the degeneration of GABAergic motor neurons.23 Mutant worms also showed stress
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sensitivity, with osmotic stress provoking motor neuron degeneration.23 The pathogenic GGGGCC repeat found in C9ORF72 is the most significant cause of familial and sporadic ALS identified thus far.3 We do not yet know the function of C9ORF72 and if it is functionally similar to other ALS genes. Importantly, for many ALS cases negative for the pathogenic GGGGCC repeat, the expression level of C9ORF72 was also reduced,24 suggesting that C9ORF72 is an important player in ALS pathogenesis. To further our understanding of C9ORF72 pathogenesis, we generated worms expressing mutant TDP-43A315T or FUSS57Δ proteins in combination with the null mutation for alfa-1. We observed that decreased expression of alfa-1 exacerbated the paralysis phenotype in worms expressing mutant TDP-43 but did not alter the toxicity of mutant FUS proteins. These results suggest that C9ORF72 functions in the same toxic pathway as FUS, and perhaps independently (or in parallel) from TDP-43. Therefore, even though FUS and TDP-43 share many structural similarities, they interact differently with alfa-1/C9ORF72 in motor neuron toxicity.
ALS Genes Link to Other Neurodegenerative Disorders? Many genes linked to ALS are also implicated in other neurodegenerative disorders. For example, many ALS proteins were found in aggregates of other neurodegenerative disorders.25-29 It is still unknown if the recruitment of proteins to aggregates is a specific pathological event or not 30 and how it could causes toxicity. It has been speculated that the recruitment of these proteins to aggregates may produce a partial loss of function at the cellular level, but many questions remain about this mechanism in regards to neuronal function and neurodegeneration. Frontotemporal dementia (FTD) also seems to be connected to many other neurodegenerative disorders. The identification of genetic mutations in C9ORF72, TARDBP, and UBQLN2 in FTD and ALS,5,8,18,31 has led to the acceptance of a continuum between these
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diseases. Furthermore, genetic mutations in MAPT, PGRN, and C9ORF72 are also the main causes of familial FTD.32 Mutations in MAPT have also been linked to a susceptibility loci of Parkinson disease33-35 and is a major player in Alzheimer disease.36 Therefore, FTD appears to network with many other neurodegenerative disorders and shares many toxic mechanisms with ALS. We think the genetic network including ALS can also incorporate polyglutamine diseases, Alzheimer, and Parkinson diseases. FUS and TDP-43 were shown to colocalize to aggregates in models of the polyglutamine expansion disorders including, Huntington’s Disease and Machado-Joseph Disease,37,38 and to interact with ATXN-239,40 the protein linked to spinocerebellar ataxia type 2. Moreover, in worms, wild-type TDP-1 and FUST-1 proteins contribute the agedependent toxicity of mutant polyglutamine proteins.41 Finally, ER stress has been a recurrent theme regarding ALS pathogenesis in many models as well as in patients.13,42 Similar toxic mechanisms were also implicated in other neurodegenerative disorders, including Parkinson disease and Alzheimer disease.43,44
Concluding Remarks In the motor neuron disease hereditary spastic paraplegia (HSP), characterization of a network including many HSP genes has proven successful in identifying new genes and novel neurodegeneration pathways.45 Furthermore, the network identified proved to be highly related to Parkinson disease, Alzheimer disease, and ALS, further suggesting a link between neurodegenerative diseases. We believe the development of a similar network regarding ALS is essential for our understanding of the disease state and for the identification of biological markers. With the recent identification of the non-coding GGGGCC repeat found in the first intron of C9ORF72 link with ALS and FTD, we continued our investigation of a genetic network among ALS genes. We have shown that a decreased expression of alfa-1/C9ORF72 enhanced the toxicity of mutant TDP-43 proteins
but not FUS.23 We suggest a genetic network (Fig. 1) that includes many genes involved in ALS and FTD where FUS and TDP-43 interact with each other but have distinct effect on C9ORF72 and PGRN17,41 Of course, much more remains to be learned about C9ORF72 biology and pathology. We still do not know why individuals will develop ALS or FTD or both. The close relationship between FTD and other neurodegenerative disorders, such as Parkinson disease and Alzheimer disease, suggest that the characterization of C9ORF72 toxicity is essential and will uncover important pathogenic mechanisms related to many neurodegenerative diseases. The involvement of C9ORF72/ ALFA-1 in the osmotic stress response and the induction of neuronal breaks by an osmotic stress are particularly interesting in this regard. The osmotic stress response is important to maintain proper cell size and protein homeostasis.46 Stress response and protein misfolding are two important aspects of ALS pathogenesis as well as in other neurodegenerative disorders. The development of a genetic network could help understand the importance of those toxic mechanisms in the neuronal loss and of the role of the participating proteins in this pathway. Disclosure of Potential Conflicts
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Deciphering genetic interactions between ALS genes using C. elegans Martine Therrien a
ab
& J Alex Parker
abc
CRCHUM; Montréal, QC Canada
b
Departement de pathologie et biologie cellulaire; Universite de Montréal; Montréal, QC Canada c
Departement de neurosciences; Universite de Montréal; Montréal, QC Canada Published online: 08 May 2014.
Click for updates To cite this article: Martine Therrien & J Alex Parker (2014) Deciphering genetic interactions between ALS genes using C. elegans, Worm, 3:2, e29047, DOI: 10.4161/worm.29047 To link to this article: http://dx.doi.org/10.4161/worm.29047
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Commentary
Worm 3, e29047; April 2014; © 2014 Landes Bioscience
Deciphering genetic interactions between ALS genes using C. elegans Martine Therrien1,2 and J Alex Parker1,2,3* CRCHUM; Montréal, QC Canada; 2Departement de pathologie et biologie cellulaire; Universite de Montréal; Montréal, QC Canada; Departement de neurosciences; Universite de Montréal; Montréal, QC Canada
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Keywords: ALS, C9ORF72, FUS, PGRN, SOD1, TDP-43, neurodegeneration *Correspondence to: J Alex Parker; Email: [email protected] Submitted: 03/05/2014 Revised: 04/14/2014 Accepted: 04/28/2014 http://dx.doi.org/10.4161/worm.29047
myotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder causing selective death of motor neurons in which it is speculated that 10% of cases have a familial history. In the past 20 years, many genes causative for ALS have been discovered, but the link between them and their roles in neurodegeneration remain unknown. The identification of genes associated with both ALS and frontotemporal dementia (FTD), along with the observation of patients affected by both diseases, have suggested that they are part of the same neurodegenerative spectrum. Investigating possible genetic interactions among ALS/FTD genes could help understand the role of these genes in neurodegeneration. To pursue this goal, our group has developed several ALS models to study potential genetic interactions. More recently, we characterized the deletion mutant alfa-1, the ortholog of C9ORF72, to evaluate the potential genetic interactions between C9ORF72/ alfa-1 and other ALS genes. Here, we discuss the genetic interactions identified in our models and how some of these proteins may also be linked to other neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing selective motor neuron loss. The disease usually starts in the lower limbs, spreading upwards causing death within 3 to 5 y after the onset of symptoms.1,2 Most cases of ALS are sporadic, but it is speculated that 10% are familial.3 Familial and sporadic ALS cases are clinically indistinguishable, thus identifying disease pathogenesis in familial cases would help understand the pathogenesis of sporadic ALS cases. High-throughput
sequencing technologies have been used to great success over the past few years to identify genetic components of ALS. This has led to the rapid identification of more than 20 genes linked to ALS.3 Among the major ALS genes are Superoxide Dismutase 1 (SOD1),4 TAR DNA Binding Protein (TARDBP),5,6 Fused in Sarcoma (FUS),7 and C9ORF72.8,9 The identification of TDP-43, SOD1, OPTN, FUS, UBQLN2, and NEFH in most aggregates seen in ALS patient tissues suggests that these proteins are involved in disease pathogenesis.10 Many hypotheses11-13 have been put forth regarding the different toxic pathways leading to neurodegeneration; however, no consensus has been reached. Perhaps, more importantly, there are no drugs that effectively slow or halt neuronal loss in ALS patients. An unfortunate recurring theme is that many drugs that were promising candidates in preclinical trials using rodent models have failed in humans.14 Many of these compounds focused on mechanisms to reduce protein aggregation or neuronal death, but recent hypotheses suggest that drugs targeting early pathogenic events could be more effective. However, since ALS diagnosis is difficult and disease progression is rapid, the identification of biological markers is essential for effective therapeutic intervention.
Genetic Interaction Among ALS Genes Many genes linked to ALS appear to have common cellular function. For example, RNA metabolism is a recurrent theme with TDP-43, FUS,
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Figure 1. An emerging genetic network for neurodegeneration. A genetic network of genes underlying neurodegeneration demonstrating the central role of genes linked to the ALS-FTD disease spectrum. Tractable genetic systems like C. elegans are essential to investigate this genetic network of neuronal degeneration. Listed are human proteins linked to disease along with their C. elegans ortholog in parentheses. Abbreviations: ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; FUS, fused in sarcoma; MAPT, microtubule associated protein tau; PGRN, progranulin; SOD1, superoxide dismutase 1; UBQLN2, ubiquilin 2.
HNRNPA2B1, SETX, HNRNPA1, and ARHGEF28 all being involved in this pathway.3 A better understanding of the normal biological roles and the specific pathways affected by mutations may shed light on pathogenic mechanisms in the disease state. Work toward this goal has been done to identify protein–protein interaction networks and protein–RNA interactions of ALS proteins. However, proteins like TDP-43 and FUS have numerous roles affecting the metabolism of thousands of RNAs.12 Also, cells have many compensating pathways, so the genes involved in ALS might not all function in the same pathway, or interact directly but rather be in pathways that have similar functions. Thus, a genetic network of ALS genes would be an essential tool to the understanding of ALS pathogenesis. Finding the relation between ALS genes could be done through the analysis of possible genetic interactions. Genetic interactions are not always easy to determine, but if genes interact it may mean they function in the same pathway or in a compensating cellular pathway.15 To study genetic pathways, model organisms are essential. Analyzing genetic interactions requires models that can
be easily genetically modified and in which phenotypes can be quickly and easily observed. An increasingly popular model with these characteristics is the nematode Caenorhabditis elegans. Our laboratory aims, with the use of different C. elegans models, to unravel some of the interactions in this putative ALS genetic network. To do so, we have developed several C. elegans models to study ALS. The expression of the mutant TDP-43A315T or FUSS57Δ proteins in the animal’s GABAergic motor neurons results in age-dependent motility defects, neurodegeneration, and increased endoplasmic reticulum (ER) stress,16,17 recapitulating important features of ALS pathogenesis. The loss-of-function mutant of tdp1, the C. elegans ortholog of TDP-43, decrease the toxicity observed in these transgenic animals, suggesting an interaction between TDP-1 and TDP-43 and TDP-1 and FUS.17 Unpublished results using fust-1, the worm ortholog of FUS, deletion mutant, also suggest that it participates in mutant TDP-43 and mutant FUS proteotoxicity. Using these models we have determined that TDP-1/TDP43 and FUST-1/FUS genetically interact and modify the progression of motor neuron degeneration. In a recent publication, we aimed to model the toxicity of C9ORF72. In patients, a pathogenic GGGGCC repeat was identified in the first intron of C9ORF72.8,18 The function of C9ORF72 is not fully known but a recent study suggests it has roles in endosomal trafficking.19 However, it is still unclear if the mutation results in a loss of function, a gain of function, or both.20 In patients, hypermethylation of the pathoghenic GGGGCC repeat was shown to decrease the expression of C9ORF72.18,21,22 To model the decreased expression of C9ORF72, we examined the C. elegans ortholog alfa-1 (ALS/FTD associated gene homolog) and a mutation harboring a deletion of the third and fourth exons of the gene leading to a drastic reduction in gene expression. Mutant alfa-1 worms exhibited motility defects leading to an age-dependent paralysis and the degeneration of GABAergic motor neurons.23 Mutant worms also showed stress
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sensitivity, with osmotic stress provoking motor neuron degeneration.23 The pathogenic GGGGCC repeat found in C9ORF72 is the most significant cause of familial and sporadic ALS identified thus far.3 We do not yet know the function of C9ORF72 and if it is functionally similar to other ALS genes. Importantly, for many ALS cases negative for the pathogenic GGGGCC repeat, the expression level of C9ORF72 was also reduced,24 suggesting that C9ORF72 is an important player in ALS pathogenesis. To further our understanding of C9ORF72 pathogenesis, we generated worms expressing mutant TDP-43A315T or FUSS57Δ proteins in combination with the null mutation for alfa-1. We observed that decreased expression of alfa-1 exacerbated the paralysis phenotype in worms expressing mutant TDP-43 but did not alter the toxicity of mutant FUS proteins. These results suggest that C9ORF72 functions in the same toxic pathway as FUS, and perhaps independently (or in parallel) from TDP-43. Therefore, even though FUS and TDP-43 share many structural similarities, they interact differently with alfa-1/C9ORF72 in motor neuron toxicity.
ALS Genes Link to Other Neurodegenerative Disorders? Many genes linked to ALS are also implicated in other neurodegenerative disorders. For example, many ALS proteins were found in aggregates of other neurodegenerative disorders.25-29 It is still unknown if the recruitment of proteins to aggregates is a specific pathological event or not 30 and how it could causes toxicity. It has been speculated that the recruitment of these proteins to aggregates may produce a partial loss of function at the cellular level, but many questions remain about this mechanism in regards to neuronal function and neurodegeneration. Frontotemporal dementia (FTD) also seems to be connected to many other neurodegenerative disorders. The identification of genetic mutations in C9ORF72, TARDBP, and UBQLN2 in FTD and ALS,5,8,18,31 has led to the acceptance of a continuum between these
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diseases. Furthermore, genetic mutations in MAPT, PGRN, and C9ORF72 are also the main causes of familial FTD.32 Mutations in MAPT have also been linked to a susceptibility loci of Parkinson disease33-35 and is a major player in Alzheimer disease.36 Therefore, FTD appears to network with many other neurodegenerative disorders and shares many toxic mechanisms with ALS. We think the genetic network including ALS can also incorporate polyglutamine diseases, Alzheimer, and Parkinson diseases. FUS and TDP-43 were shown to colocalize to aggregates in models of the polyglutamine expansion disorders including, Huntington’s Disease and Machado-Joseph Disease,37,38 and to interact with ATXN-239,40 the protein linked to spinocerebellar ataxia type 2. Moreover, in worms, wild-type TDP-1 and FUST-1 proteins contribute the agedependent toxicity of mutant polyglutamine proteins.41 Finally, ER stress has been a recurrent theme regarding ALS pathogenesis in many models as well as in patients.13,42 Similar toxic mechanisms were also implicated in other neurodegenerative disorders, including Parkinson disease and Alzheimer disease.43,44
Concluding Remarks In the motor neuron disease hereditary spastic paraplegia (HSP), characterization of a network including many HSP genes has proven successful in identifying new genes and novel neurodegeneration pathways.45 Furthermore, the network identified proved to be highly related to Parkinson disease, Alzheimer disease, and ALS, further suggesting a link between neurodegenerative diseases. We believe the development of a similar network regarding ALS is essential for our understanding of the disease state and for the identification of biological markers. With the recent identification of the non-coding GGGGCC repeat found in the first intron of C9ORF72 link with ALS and FTD, we continued our investigation of a genetic network among ALS genes. We have shown that a decreased expression of alfa-1/C9ORF72 enhanced the toxicity of mutant TDP-43 proteins
but not FUS.23 We suggest a genetic network (Fig. 1) that includes many genes involved in ALS and FTD where FUS and TDP-43 interact with each other but have distinct effect on C9ORF72 and PGRN17,41 Of course, much more remains to be learned about C9ORF72 biology and pathology. We still do not know why individuals will develop ALS or FTD or both. The close relationship between FTD and other neurodegenerative disorders, such as Parkinson disease and Alzheimer disease, suggest that the characterization of C9ORF72 toxicity is essential and will uncover important pathogenic mechanisms related to many neurodegenerative diseases. The involvement of C9ORF72/ ALFA-1 in the osmotic stress response and the induction of neuronal breaks by an osmotic stress are particularly interesting in this regard. The osmotic stress response is important to maintain proper cell size and protein homeostasis.46 Stress response and protein misfolding are two important aspects of ALS pathogenesis as well as in other neurodegenerative disorders. The development of a genetic network could help understand the importance of those toxic mechanisms in the neuronal loss and of the role of the participating proteins in this pathway. Disclosure of Potential Conflicts
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