Reversing lysosome-ribosome circuit dysregulation mitigates C9FTD/ALS neurodegeneration and behaviors.
Publication Year:
2023
PubMed ID:
36322143
Funding Grants:
Public Summary:
A genetic mutation involving G4C2 repeat expansion in the C9ORF72 gene is responsible for a common form of familial frontotemporal dementia and amyotrophic lateral sclerosis (C9FTD/ALS). The disease arises from a combination of factors, including a deficiency in the C9ORF72 gene and the toxic effects of the G4C2 repeat expansion. Researchers have used a mouse model to understand the disease mechanisms better. In this study, they found that C9orf72 deficiency worsens FTD/ALS-like symptoms in mice with the G4C2 repeat mutation. Importantly, when they introduced C9ORF72 or its partner Smcr8, into the mutant mice, it improved lysosomal function, normalized gene expression and reduced the toxic effects of the G4C2 repeats. This intervention also mitigated neurodegeneration and behavioral problems similar to FTD/ALS. In summary, this study reveals that in C9FTD/ALS, proteins work together to disrupt a crucial lysosome-ribosome biogenesis circuit in neurons. This disruption leads to cellular stress, neurodegeneration, and the behavioral symptoms associated with the disease
Scientific 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 G4C2 repeats under endogenous regulatory elements from patients. Single nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq revealed that C9orf72 depletion disrupts lysosomes in neurons and leads to transcriptional dysregulation of ribosomal protein genes, which are likely due to the proteotoxic stress response and resemble ribosomopathy defects. Importantly, ectopic expression of C9orf72 or its partner Smcr8 in C9FTD/ALS mutant mice promotes lysosomal functions and restores ribosome biogenesis gene transcription, resulting in the mitigation of DPR accumulation, neurodegeneration as well as FTD/ALS-like motor and cognitive behaviors. Therefore, we conclude that loss- and gain-of-function crosstalk in C9FTD/ALS converges on neuronal dysregulation of a lysosome-ribosome biogenesis circuit leading to proteotoxicity, neurodegeneration and behavioral defects.