Document Type
Article
Publication 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.
Recommended Citation
Verdone, 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.
https://jdc.jefferson.edu/department_neuroscience/66
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Language
English
Comments
This article is the author’s final published version in Scientific Reports, Volume 12, Issue 1, April 2022, Article number 5644.
The published version is available at https://doi.org/10.1038/s41598-022-09593-z. Copyright © Verdone et al.