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

Qiang Zhu¹, Jie Jiang¹, Tania F. Gendron⁴, Melissa McAlonis-Downes¹, Patrick King¹, Marcus Maldonado¹, Amy Taylor³, Sandra Diaz Garcia³, Maria J. Rodriguez³, Brian Myers¹, Somasish Ghosh Dastidar^5,6, Jeesun Kim³, Charles Heyser³, Albert R. La Spada^5,6, Leonard Petrucelli⁴, Sandrine Da Cruz¹, John Ravits³, Clotilde Lagier-Tourenne^1,7,8andDon W. Cleveland^1-3
¹Ludwig Institute for Cancer Research and Departments of ²Cellular and Molecular Medicine, ³Neurosciences, ⁵Pediatrics, University of California at San Diego, La Jolla, CA 92093, USA; ⁴Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA; ⁶Departments of Neurology, Neurobiology, and Cell Biology, Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine, Durham, NC, 27710, USA;⁷Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; ⁸Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA

Hexanucleotide GGGGCC 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 produce one or more toxic products, in affected individuals the repeat expansion also reduces mRNAs encoding C9ORF72, a predicted guanine exchange factor. Using mice that express a human C9ORF72 gene with 450 repeats but which does not encode the C9ORF72 protein, we determine that disruption of one or both endogenous C9ORF72 alleles enhances cognitive deficits, hippocampal neuron loss, and glial activation. Reduction in C9ORF72 is also found to suppress repeat-mediated elevation in autophagy, accompanied by accelerated accumulation of dipeptide-repeat proteins produced by AUG-independent translation of repeat-containing RNAs. These efforts provide direct support for disease mechanism in ALS/FTD from reduced C9ORF72 function synergizing with repeat-dependent gain-of-toxicity.

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