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


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.


Amyotrophic lateral sclerosis Genes Ubiquitin Proteasome Autophagy Aggregates 



Motor neuron


Amyotrophic lateral sclerosis


Ubiquitin proteasome system


Endoplasmic reticulum-associated protein degradation


Chaperone-assisted proteasomal degradation


Chaperone-mediated autophagy


Chaperone-assisted selective autophagy




Small ubiquitin-like modifier


Stress granules


Chromosome 9 open reading frame 72


Superoxide dismutase 1


TAR DNA-binding protein


Fused in sarcoma






Valosin-containing protein


Ubiquilin 2


Vesicle-associated membrane protein-associated protein B/C


TANK-binding kinase 1


FIG4 phosphoinositide 5-phosphatase


Sigma non-opioid intracellular receptor 1


Cyclin F


Protein disulfide isomerase family A member



This work is supported by the Region Centre Val-de-Loire, the Association ARSLA, and the MAbImprove Laboratoire d’excellence (Labex).


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.UMR INSERM U1253Université de ToursToursFrance
  2. 2.Service de NeurologieCHRU de ToursToursFrance
  3. 3.Service de Biochimie et de Biologie MoléculaireCHRU de ToursToursFrance

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