Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo

Cell Rep. 2020 May 5;31(5):107616. doi: 10.1016/j.celrep.2020.107616.

Abstract

A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.

Keywords: ALS; C9orf72; FTD; RAN translation; RNA foci; SCA36; TDP-43; mouse; poly(GP); poly(PR).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • C9orf72 Protein / genetics*
  • DNA Repeat Expansion / genetics
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Humans
  • Inclusion Bodies / metabolism
  • Mice
  • Neurons / metabolism
  • Nuclear Proteins / genetics*
  • RNA / metabolism*

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • C9orf72 protein, mouse
  • NOP56 protein, human
  • Nuclear Proteins
  • RNA