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NEURODEGENERATION

Realizing the gains and losses in C9ORF72 ALS/FTD

Nature Neuroscience volume 23, pages 596–597 (2020)Cite this article

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At the heart of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (ALS /FTD) research lies the mechanistic question of whether disease is caused by toxic gain of function related to the repeat expansion, loss of endogenous C9ORF72 expression, or both. New findings provide insights to this question.

Repeat expansions in the C9ORF72 gene are the predominant cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)1 Adding to the excitement of this discovery was the recognized potential to apply therapeutic strategies involving ‘knock-down’ or altered expression of the dominant disease-causing allele. Recent US Food and Drug Agency (FDA) approvals in antisense oligonucleotide (ASO) therapeutics in spinal muscular atrophy and Duchene muscular dystrophy, with additional encouraging clinical trial data in SOD1 inherited ALS, have galvanized the research community in their focus toward these tangible therapeutics. Based in part on positive preclinical data from transgenic mice, ASO therapies in C9ORF72 ALS/FTD has moved quickly beyond ideation and into development, with Biogen recently announcing plans involving a phase 1 safety trial2. Still, a growing base of evidence supports the hypothesis that C9ORF72 ALS/FTD is related to a loss of function of endogenous C9ORF72 gene expression and not simply a dominant gain of function caused by the repeat expansion. This debate between loss and gain of function in C9ORF72 pathogenesis may have ended with research findings published in Nature Neuroscience by Zhu and colleagues3. The answer they found: it’s both.

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Fig. 1: C9orf72 pathology may be a synergy of loss- and gain-of-function mechanisms.

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  1. The Jackson Laboratory, Bar Harbor, ME, USA

    Cathleen Lutz

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  1. Cathleen Lutz
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Correspondence to Cathleen Lutz.

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Lutz, C. Realizing the gains and losses in C9ORF72 ALS/FTD. Nat Neurosci 23, 596–597 (2020). https://doi.org/10.1038/s41593-020-0622-x

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