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C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?

Authors
  • Braems, Elke1, 2
  • Swinnen, Bart1, 2, 3
  • Van Den Bosch, Ludo1, 2
  • 1 KU Leuven-University of Leuven,
  • 2 VIB,
  • 3 University Hospitals Leuven,
Type
Published Article
Journal
Acta Neuropathologica
Publisher
Springer-Verlag
Publication Date
Sep 02, 2020
Volume
140
Issue
5
Pages
625–643
Identifiers
DOI: 10.1007/s00401-020-02214-x
PMID: 32876811
PMCID: PMC7547039
Source
PubMed Central
Keywords
License
Unknown

Abstract

A repeat expansion in C9orf72 is responsible for the characteristic neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in a still unresolved manner. Proposed mechanisms involve gain-of-functions, comprising RNA and protein toxicity, and loss-of-function of the C9orf72 gene. Their exact contribution is still inconclusive and reports regarding loss-of-function are rather inconsistent. Here, we review the function of the C9orf72 protein and its relevance in disease. We explore the potential link between reduced C9orf72 levels and disease phenotypes in postmortem, in vitro, and in vivo models. Moreover, the significance of loss-of-function in other non-coding repeat expansion diseases is used to clarify its contribution in C9orf72 ALS/FTD. In conclusion, with evidence pointing to a multiple-hit model, loss-of-function on itself seems to be insufficient to cause neurodegeneration in C9orf72 ALS/FTD.

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