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Causative Genes in Amyotrophic Lateral Sclerosis and Protein Degradation Pathways: a Link to Neurodegeneration

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Abstract

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.

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Abbreviations

MN:

Motor neuron

ALS:

Amyotrophic lateral sclerosis

UPS:

Ubiquitin proteasome system

ERAD:

Endoplasmic reticulum-associated protein degradation

CAP:

Chaperone-assisted proteasomal degradation

CMA:

Chaperone-mediated autophagy

CASA:

Chaperone-assisted selective autophagy

Ub:

Ubiquitin

SUMO:

Small ubiquitin-like modifier

SG:

Stress granules

C9ORF72:

Chromosome 9 open reading frame 72

SOD1:

Superoxide dismutase 1

TARDBP:

TAR DNA-binding protein

FUS:

Fused in sarcoma

OPTN:

Optineurin

SQSTM1:

p62/sequestosome1

VCP:

Valosin-containing protein

UBQNL2:

Ubiquilin 2

VAPB:

Vesicle-associated membrane protein-associated protein B/C

TBK1:

TANK-binding kinase 1

FIG4:

FIG4 phosphoinositide 5-phosphatase

SIGMAR1:

Sigma non-opioid intracellular receptor 1

CCNF:

Cyclin F

PDIA:

Protein disulfide isomerase family A member

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Acknowledgments

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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Authors and Affiliations

  1. UMR INSERM U1253, Université de Tours, 37032, Tours, France

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

  2. Service de Neurologie, CHRU de Tours, 37044, Tours, France

    P. Corcia

  3. Service de Biochimie et de Biologie Moléculaire, CHRU de Tours, 37044, Tours, France

    H. Blasco, C. R. Andres & P. Vourc’h

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  1. C. Maurel
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Maurel, C., Dangoumau, A., Marouillat, S. et al. Causative Genes in Amyotrophic Lateral Sclerosis and Protein Degradation Pathways: a Link to Neurodegeneration. Mol Neurobiol 55, 6480–6499 (2018). https://doi.org/10.1007/s12035-017-0856-0

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