Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these mice, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. We suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress.
Recommended CitationVerdone, Brandie Morris; Cicardi, Maria Elena; Wen, Xinmei; Sriramoji, Sindhu; Russell, Katelyn; Markandaiah, Shashirekha S; Jensen, Brigid K; Krishnamurthy, Karthik; Haeusler, Aaron R.; Pasinelli, Piera; and Trotti, Davide, "A mouse model with widespread expression of the C9orf72-linked glycine-arginine dipeptide displays non-lethal ALS/FTD-like phenotypes" (2022). Department of Neuroscience Faculty Papers. Paper 66.
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