C9orf72-mediated ALS and FTD: multiple pathways to disease

By R. Balendra, A. Isaacs. Nature Reviews Neurology, 2018

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The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.Repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Balendra and Isaacs review the pathological and mechanistic features of C9orf72-associated ALS and FTD, highlighting loss-of-function, gain-of-function and downstream mechanisms.Key pointsRapid progress has been made in the understanding of how repeat expansions in C9orf72 cause C9orf72-associated frontotemporal dementia and/or amyotrophic lateral sclerosis (C9FTD/ALS).Both loss of function of C9orf72 and gain of toxic function of the repeats are implicated in C9FTD/ALS.A range of new models, including mice, Drosophila and patient neurons, have provided new insights into the disease mechanisms.Several cellular pathways are affected in C9FTD/ALS and could provide new options for treatment.Targeted therapeutic strategies against the repeats themselves are the most advanced and are progressing towards clinical trials.

Subfields: Genetics, Neurology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/34e1714a970256b9bcadbd82b3c7e7708de1ce8d