Proteostasis deregulation as a driver of C9ORF72 pathogenesis

J Neurochem. 2021 Dec;159(6):941-957. doi: 10.1111/jnc.15529. Epub 2021 Nov 9.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G4 C2 ) in C9ORF72 gene has been causally linked to both ALS and FTD emergence, thus opening a novel potential therapeutic target for disease intervention. The main driver of C9ORF72 pathology is the disruption of distinct cellular processes involved in the function of the proteostasis network. Here we discuss main findings relating to the induction of neurodegeneration by C9ORF72 mutation and proteostasis deregulation, highlighting the role of the endoplasmic reticulum stress, nuclear transport, and autophagy in the disease process. We further discuss possible points of intervention to target proteostasis mediators to treat C9ORF72-linked ALS/FTD.

Keywords: ALS; C9ORF72; ER stress; FTD; ISR; UPR; proteostasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Autophagy / physiology
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism*
  • Endoplasmic Reticulum Stress / physiology
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • Frontotemporal Dementia / pathology
  • Humans
  • Proteostasis / physiology*

Substances

  • C9orf72 Protein
  • C9orf72 protein, human