A Mouse Model with Widespread Expression of the C9orf72-Linked Glycine-Arginine Dipeptide Displays Non-Lethal ALS/FTD-Like Phenotypes
Abstract Background: 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. Yet, there is much to learn about the contribution of DPRs to disease pathogenesis, as not all DPRs function and localize within cells in the same manner, nor are they all the same repeat length. These phenomena create a heterogeneity that confounds the study of their toxic consequences. Methods: In vitro transfection of different lengths of the toxic DPR glycine-arginine (poly-GR) was used to determine a relevant pathogenic length for in vivo assessment. We then generated a novel transgenic mouse expressing poly-GR under a ubiquitous promoter for histological characterization and assessment of motor and cognitive behaviors. Results: We identify a short repeat length in vitro that, when expressed, correlates with a reduction in cell survival over an extended period. In vivo, we observe sex-specific chronic ALS/FTD-like phenotypes in our transgenic mice expressing the same short-length DPR, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. Despite the chronic phenotype, survival of these animals is not affected over 12 months. Conclusions: We show that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is 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 conclude that this short length poly-GR induces a chronic, but non-lethal phenotype in our mouse model and suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress.