Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia

Delia Gagliardi, Gianluca Costamagna, Michela Taiana, Luca Andreoli, Fabio Biella, Margherita Bersani, Nereo Bresolin, Giacomo Pietro Comi, Stefania Corti

Research output: Contribution to journalReview articlepeer-review

Abstract

In 2011, a hexanucleotide repeat expansion (HRE) in the noncoding region of C9orf72 was associated with the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The main pathogenic mechanisms in C9-ALS/FTD are haploinsufficiency of the C9orf72 protein and gain of function toxicity from bidirectionally-transcribed repeat-containing RNAs and dipeptide repeat proteins (DPRs) resulting from non-canonical RNA translation. Additionally, abnormalities in different downstream cellular mechanisms, such as nucleocytoplasmic transport and autophagy, play a role in pathogenesis. Substantial research efforts using in vitro and in vivo models have provided valuable insights into the contribution of each mechanism in disease pathogenesis. However, conflicting evidence exists, and a unifying theory still lacks. Here, we provide an overview of the recently published literature on clinical, neuropathological and molecular features of C9-ALS/FTD. We highlight the supposed neuronal role of C9orf72 and the HRE pathogenic cascade, mainly focusing on the contribution of RNA foci and DPRs to neurodegeneration and discussing the several downstream mechanisms. We summarize the emerging biochemical and neuroimaging biomarkers, as well as the potential therapeutic approaches. Despite promising results, a specific disease-modifying treatment is still not available to date and greater insights into disease mechanisms may help in this direction.

Original languageEnglish
Article number101172
JournalAgeing Research Reviews
Volume64
DOIs
Publication statusPublished - Dec 2020

Keywords

  • Amyotrophic lateral sclerosis
  • C9orf72
  • Dipeptide repeat proteins
  • Downstream mechanisms
  • RNA foci
  • Therapeutic approaches

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Ageing
  • Molecular Biology
  • Neurology

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