Description
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 Dastidar5,6, Jeesun Kim3, Charles Heyser3, Albert R. La Spada5,6, Leonard Petrucelli4, Sandrine Da Cruz1, John Ravits3, Clotilde Lagier-Tourenne1,7,8 and Don W. Cleveland1-3
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.