The C9ORF72 repeat expansion alters neurodevelopment

Cell Rep. 2023 Aug 29;42(8):112983. doi: 10.1016/j.celrep.2023.112983. Epub 2023 Aug 16.

Abstract

Genetic mutations that cause adult-onset neurodegenerative diseases are often expressed during embryonic stages, but it is unclear whether they alter neurodevelopment and how this might influence disease onset. Here, we show that the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), a repeat expansion in C9ORF72, restricts neural stem cell proliferation and reduces cortical and thalamic size in utero. Surprisingly, a repeat expansion-derived dipeptide repeat protein (DPR) not known to reduce neuronal viability plays a key role in impairing neurodevelopment. Pharmacologically mimicking the effects of the repeat expansion on neurodevelopment increases susceptibility of C9ORF72 mice to motor defects. Thus, the C9ORF72 repeat expansion stunts development of the brain regions prominently affected in C9ORF72 FTD/ALS patients.

Keywords: C9ORF72; CP: Neuroscience; amyotrophic lateral sclerosis; frontotemporal dementia; induced pluripotent stem cells; neural stem cells; neurodevelopment.

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
  • Animals
  • C9orf72 Protein* / genetics
  • Dipeptides
  • Disease Models, Animal
  • Frontotemporal Dementia* / genetics
  • Mice
  • Mutation

Substances

  • C9orf72 Protein
  • C9orf72 protein, mouse
  • Dipeptides