Amyotrophic Lateral Sclerosis Pathogenesis Converges on Defects in Protein Homeostasis Associated with TDP-43 Mislocalization and Proteasome-Mediated Degradation Overload

Curr Top Dev Biol. 2017;121:111-171. doi: 10.1016/bs.ctdb.2016.07.004. Epub 2016 Aug 13.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects upper and/or lower motor neurons. It usually affects people between the ages of 40-70. The average life expectancy is about 3-5 years after diagnosis and there is no effective cure available. Identification of variants in more than 20 different loci has provided insight into the pathogenic molecular mechanisms mediating disease pathogenesis. In this review, we focus on seven ALS-causing genes: TDP-43, FUS, C9orf72, VCP, UBQLN2, VAPB and SOD-1, which encompass about 90% of the variants causing familial ALS. We examine the biological functions of these genes to assess how these pathogenic variants contribute to ALS pathogenesis by integrating findings from studies in Drosophila melanogaster and mammals. Additionally, we highlight the functional and genetic connections between these loci. Altogether, this review reveals that the majority of biological studies converge on defects in proteostasis due to the mislocalization of TDP-43 and/or altering the function of specific proteins mediating or modulating proteasomal degradation.

Keywords: C9orf72; Drosophila; ERAD; FUS; Neurodegeneration; Proteostasis; SOD-1; UBQLN; VAPB; VCP.

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • DNA-Binding Proteins / metabolism*
  • Homeostasis*
  • Humans
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis*
  • RNA Processing, Post-Transcriptional


  • DNA-Binding Proteins
  • Proteasome Endopeptidase Complex