biostudies-literatureVerdone BMNIA NIH HHSThe Professor Fredric Rieders, PhD scholarshipNINDS NIH HHSNational Institutes of HealthNIH HHSMuscular Dystrophy Association5644https://www.ebi.ac.uk/biostudies/studies/S-EPMC8979946biostudies-literatureUnknown12(1)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.Scientific reportsA mouse model with widespread expression of the C9orf72-linked glycine-arginine dipeptide displays non-lethal ALS/FTD-like phenotypes.PMC8979946RF1-NS114128628389RF1 AG057882R01-NS109150RF1 NS114128R21-NS090912Verdone BMCicardi MEWen XSriramoji SKrishnamurthy KTrotti DMarkandaiah SSHaeusler ARJensen BKPasinelli PRussell KfalseA mouse model with widespread expression of the C9orf72-linked glycine-arginine dipeptide displays non-lethal ALS/FTD-like phenotypes.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.2022-01-01T00:00:00Z2022 Apr2025-04-26T15:15:05.11Z2025-04-06T14:51:05.508ZS-EPMC89799463537987610.1038/s41598-022-09593-z