Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis: Converging roads to therapeutic development

Melissa Bowerman, Lyndsay M. Murray, Frederique Scamps, Bernard L. Schneider, Rashmi Kothary, Cedric Raoul*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72). However, it has come to light that these two diseases may be more interlinked than previously thought. Indeed, it has recently been found that FUS directly interacts with an Smn-containing complex, mutant SOD1 perturbs Smn localization, Smn depletion aggravates disease progression of ALS mice, overexpression of SMN in ALS mice significantly improves their phenotype and lifespan, and duplications of SMN1 have been linked to sporadic ALS. Beyond genetic interactions, accumulating evidence further suggests that both diseases share common pathological identities such as intrinsic muscle defects, neuroinflammation, immune organ dysfunction, metabolic perturbations, defects in neuron excitability and selective motoneuron vulnerability. Identifying common molecular effectors that mediate shared pathologies in SMA and ALS would allow for the development of therapeutic strategies and targeted gene therapies that could potentially alleviate symptoms and be equally beneficial in both disorders. In the present review, we will examine our current knowledge of pathogenic commonalities between SMA and ALS, and discuss how furthering this understanding can lead to the establishment of novel therapeutic approaches with wide-reaching impact on multiple motoneuron diseases.

Original languageEnglish
Pages (from-to)685-698
Number of pages14
JournalEuropean journal of medical genetics
Volume61
Issue number11
Early online date5 Dec 2017
DOIs
Publication statusPublished - Nov 2018

Keywords

  • MOTOR-NEURON PROTEIN
  • MUSCLE SATELLITE CELLS
  • RANDOMIZED CONTROLLED-TRIAL
  • ALPHA-SYNUCLEIN PROTECTS
  • WERDNIG-HOFFMANN-DISEASE
  • TRANSGENIC MOUSE MODEL
  • CENTRAL-NERVOUS-SYSTEM
  • HUMAN SPORADIC ALS
  • EXTENDS LIFE-SPAN
  • MUTANT SOD1 MICE

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