An amyloid-like cascade hypothesis for C9orf72 ALS/FTD

Area of Science:

• Neurobiology
• Genetics
• Molecular Biology

Background:

• C9orf72 GGGGCC repeat expansion is a leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Pathogenic mechanisms involve repeat RNA transcripts and their translation into toxic dipeptide repeat (DPR) proteins.

Purpose of the Study:

• To elucidate the molecular cascade initiated by C9orf72 repeat expansion.
• To understand the roles of repeat RNA and DPRs in neurodegeneration and TDP-43 pathology.

Main Methods:

• Analysis of repeat RNA and DPR protein interactions.
• Investigation of effects on cellular transport and protein aggregation.
• Comparison with Alzheimer's disease pathogenesis.

Main Results:

• Bidirectional repeat transcripts form nuclear RNA foci, sequestering RNA-binding proteins.
• DPR proteins inhibit proteasomal function and sequester other cellular proteins.
• Both repeat RNA and DPRs impair nucleocytoplasmic transport and induce TDP-43 mislocalization and aggregation.
• These molecular events precede brain atrophy and cognitive impairment.

Conclusions:

• The C9orf72 repeat expansion triggers a cascade involving repeat RNA and DPRs, leading to TDP-43 pathology and neurodegeneration.
• This cascade shares similarities with amyloid-β peptide-induced pathology in Alzheimer's disease.
• Targeting components of the C9orf72 cascade offers potential therapeutic strategies for ALS and FTD.