Genetics of amyotrophic lateral sclerosis

Corcia, Philippe; Couratier, Philippe; Blasco, Hélène; Andres, Christian R.; Beltran, S.; Meininger, Vincent; Vourc’h, Patrick

doi:10.1016/j.neurol.2017.03.030

Cited by 56 publications

(32 citation statements)

References 77 publications

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“…Mutations in Cu/Zn superoxide dismutase 1 (SOD1), the first identified gene in ALS, characterize more than 20% of familial and 1–4% of sporadic ALS cases ( 1 , 2 ). To date, more than 20 gene mutations have been identified in familial ALS, and hexarepeat expansion on chromosome 9 open reading frame 72 (C9orf72) is reported to be the most frequent genetic cause of familial ALS (40%) ( 2 , 3 ). Scientific advances in genetic studies have enabled the identification of genes contributing to ALS pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

2017

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease.

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Section: Introductionmentioning

confidence: 99%

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

2017

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“…The cellular processes, including RNA processing, protein degradation pathways, ubiquitin-proteasome system (UPS), autophagy, and so on, are all reported related to ALS pathogenesis [1][2][3][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Sorted by the various processes, we summarize the causative genes and genes might increase susceptibility of ALS which impact physiological activities mentioned above (Figure 1).…”

Section: Pathogenesis Of Als-related Genesmentioning

confidence: 99%

Novel Aspects on Motor Neuron Disease: The Recent Genetic Studies on ALS

Wang¹

2020

Novel Aspects on Motor Neuron Disease

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At present, with the advanced affordable genetic testing, the rate of discovering amyotrophic lateral sclerosis (ALS)-related genes rapidly increases. These genetic findings provide new insights into therapies that target genetic subset of ALS. However, the research on the genetic and environmental causes of ALS is still in the early stage. In this chapter, we review the current understanding of ALS-related genes and summarize the worldwide ALS distribution feature by the frequency of occurrence in different regions. We summarize the advances in genetic testing and counseling for ALS. Based on the increase in genetic testing, we believe that the ALS patients and families would be benefited from our studies in the near future.

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“…The consequences of protein misfolding in neuronal cells can include neurodegeneration, in which case misfolded proteins are implicated in each disorder that have pathological effects in specific neuronal populations [52]. We tested the binding of HSC70 and HSP70 to one of these factors, the superoxide dismutase mutant A4V (SOD1 A4V) associated with a subset of familial ALS and the cause of highly penetrant and rapid motor neuron loss [53]. The A4V mutation in SOD1 promotes the formation of misfolded but soluble oligomers that are thought to be associated with neurotoxicity [54].…”

Section: Expression Of a Misfolded Protein Changes The Landscape Of Hmentioning

confidence: 99%

Comprehensive identification of HSP70/HSC70 Chaperone Clients in Human Cells

Ryu

Stewart

Pectol

et al. 2019

Preprint

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The HSP70 family of chaperones are the front-line of protection from stress-induced misfolding and aggregation of polypeptides in most organisms and are responsible for promoting the stability, folding, and degradation of clients to maintain cellular protein homeostasis. Here we demonstrate quantitative identification of HSP70 and HSC70 clients using an ubiquitin-mediated proximity tagging strategy and show that, despite their high degree of similarity, these enzymes have largely non-overlapping specificities. Both proteins show a preference for association with newly synthesized polypeptides but each responds differently to changes in the stoichiometry of proteins in obligate multi-subunit complexes. In addition, expression of an ALS-associated SOD1 mutant protein induces changes in HSP70 and HSC70 client association and aggregation toward polypeptides with predicted disorder, indicating that there are global effects from a single misfolded protein that extend to many clients within chaperone networks. Together these findings show that the ubiquitin-mediated UBAIT fusion system can efficiently isolate the complex interactome of HSP chaperone family proteins under normal and stress conditions.

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Genetics of amyotrophic lateral sclerosis

Cited by 56 publications

References 77 publications

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

Novel Aspects on Motor Neuron Disease: The Recent Genetic Studies on ALS

Comprehensive identification of HSP70/HSC70 Chaperone Clients in Human Cells

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