A mouse model with widespread expression of the C9orf72-linked glycine-arginine dipeptide displays non-lethal ALS/FTD-like phenotypes.
Publication/Presentation Date
4-4-2022
Abstract
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.
Volume
12
Issue
1
First Page
5644
Last Page
5644
ISSN
2045-2322
Published In/Presented At
Verdone, B. M., Cicardi, M. E., Wen, X., Sriramoji, S., Russell, K., Markandaiah, S. S., Jensen, B. K., Krishnamurthy, K., Haeusler, A. R., Pasinelli, P., & Trotti, D. (2022). A mouse model with widespread expression of the C9orf72-linked glycine-arginine dipeptide displays non-lethal ALS/FTD-like phenotypes. Scientific reports, 12(1), 5644. https://doi.org/10.1038/s41598-022-09593-z
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
35379876
Department(s)
Administration and Leadership
Document Type
Article