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

Qiang Zhu, Jie Jiang, Tania F. Gendron, Melissa McAlonis-Downes, Lulin Jiang, Amy Taylor, Sandra Diaz Garcia, Somasish Ghosh Dastidar, Maria J. Rodriguez, Patrick King, Yongjie Zhang, Albert R. La Spada, Huaxi Xu, Leonard Petrucelli, John Ravits, Sandrine Da Cruz, Clotilde Lagier-Tourenne, Don W. Cleveland

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity.

Original languageEnglish (US)
Pages (from-to)615-624
Number of pages10
JournalNature Neuroscience
Volume23
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Neuroscience(all)

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