Causative genes in amyotrophic lateral sclerosis and protein degradation pathways: a link to neurodegeneration

C. Maurel, A. Dangoumau, S. Marouillat, C. Brulard, A. Chami, R. Hergesheimer, P. Corcia, H. Blasco, C. R. Andres, P. Vourc’h*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

56 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a disease caused by the degeneration of motor neurons (MNs) leading to progressive muscle weakness and atrophy. Several molecular pathways have been implicated, such as glutamate-mediated excitotoxicity, defects in cytoskeletal dynamics and axonal transport, disruption of RNA metabolism, and impairments in proteostasis. ALS is associated with protein accumulation in the cytoplasm of cells undergoing neurodegeneration, which is a hallmark of the disease. In this review, we focus on mechanisms of proteostasis, particularly protein degradation, and discuss how they are related to the genetics of ALS. Indeed, the genetic bases of the disease with the implication of more than 30 genes associated with familial ALS to date, together with the important increase in understanding of endoplasmic reticulum (ER) stress, proteasomal degradation, and autophagy, allow researchers to better understand the mechanisms underlying the selective death of motor neurons in ALS. It is clear that defects in proteostasis are involved in this type of cellular degeneration, but whether or not these mechanisms are primary causes or merely consequential remains to be clearly demonstrated. Novel cellular and animal models allowing chronic expression of mutant proteins, for example, are required. Further studies linking genetic discoveries in ALS to mechanisms of protein clearance will certainly be crucial in order to accelerate translational and clinical research towards new therapeutic targets and strategies.

Original languageEnglish
Pages (from-to)6480-6499
Number of pages20
JournalMolecular Neurobiology
Issue number8
Publication statusPublished - 1 Aug 2018
Externally publishedYes


  • Aggregates
  • Amyotrophic lateral sclerosis
  • Autophagy
  • Genes
  • Proteasome
  • Ubiquitin


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