Reduced C9ORF72 function exacerbates gain-of-toxicity from ALS/FTD-causing repeat expansion in C9orf72

Dastidar, Somasish Ghosh (2020) Reduced C9ORF72 function exacerbates gain-of-toxicity from ALS/FTD-causing repeat expansion in C9orf72. Nature Neuroscience, 23 (5). pp. 615-624. ISSN 1546-1726

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Abstract

Hexanucleotide expansions in C9orf72 are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein, a predicted guanine exchange factor, are also reduced in affected individuals. We now test how C9ORF72 protein levels affect repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provokes or accelerates, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that does not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbates cognitive deficits, hippocampal neuron loss, glial activation, and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 is shown to suppress repeat-mediated elevation in autophagy. These efforts suggest a disease mechanism in ALS/FTD resulting from reduced C9ORF72 producing autophagy deficits that synergize with repeat-dependent gain-oftoxicity.

Item Type: Article
Subjects: Medicine > KMC Manipal > Anatomy
Depositing User: KMC Library
Date Deposited: 27 Jun 2021 06:00
Last Modified: 27 Jun 2021 06:00
URI: http://eprints.manipal.edu/id/eprint/156813

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