A U.S. research team has revealed that repeat expansions in the C9orf72 gene — a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) — induce dysfunction of the nuclear pore complex (NPC) in neurons. In C9orf72 mutant mouse models, structural abnormalities of the NPC were observed early, leading to disrupted nucleocytoplasmic transport.
Importantly, impaired nuclear transport was closely linked to the progression of motor neuron degeneration, positioning NPC dysfunction as a central pathogenic mechanism in ALS/FTD. This finding suggests potential new therapeutic targets for these neurodegenerative disorders.
Source: Nature (June 2025), Article Link
【My Thoughts】
While prior studies of C9orf72-related ALS/FTD focused on RNA toxicity and dipeptide repeat proteins, the involvement of direct nuclear pore complex dysfunction adds a compelling new layer. The NPC may represent a convergent mechanism across multiple neurodegenerative diseases, warranting further exploration as a therapeutic target.
