Reversing lysosome-ribosome circuit dysregulation mitigates C9FTD/ALS neurodegeneration and behaviors.

ABSTRACT: G4C2 repeat expansion in C9orf72 causes the most common familial frontotemporal dementia and amyotrophic lateral sclerosis (C9FTD/ALS). The pathogenesis includes haploinsufficiency of C9orf72, which forms a protein complex with Smcr8, as well as G4C2 repeat-induced gain of function including toxic dipeptide repeats (DPRs). The key in vivo disease-driving mechanisms and how loss- and gain-of-function interplay remain poorly understood. Here, we identified dysregulation of a lysosome-ribosome biogenesis circuit as an early and key disease mechanism using a physiologically relevant mouse model with combined loss- and gain-of-function across the aging process. C9orf72 deficiency exacerbates FTD/ALS-like pathologies and behaviors in C9ORF72 bacterial artificial chromosome (C9-BAC) mice with G4C

SUBMITTER: Ma L 

PROVIDER: S-EPMC10077508 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature