Identification of Age-Associated Upstream Regulators to Promote Neuronal Resilience in HD Patient-Derived Neurons

Aging is a risk factor for neurodegenerative disorders, but the molecular link between neuronal aging and neurodegeneration remains unclear. Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms. Striatal medium spiny neurons (MSNs) are mainly affected in HD, but how aging contributes to MSN degeneration remains uncertain. Using directly converted MSNs from fibroblasts of HD patients (HD-MSNs), we studied age-related pathological features, including neuronal cell death, mutant huntingtin (mHTT) aggregation, and DNA damage in HD. In this study, through transcriptomic analysis of longitudinally aged MSNs and HD-MSNs, we identified four upstream regulators, NFKB1, SOD1, IRF3, and REST, that modulate downstream gene expression in aged MSNs. Among these, knocking down NFKB1 significantly reduced HD pathologies in HD-MSNs, while overexpressing NFKB1 reversed these protective effects. Overall, these results identify NFKB1 as a key age-associated upstream regulator whose downregulation confers neuronal resilience and is a potential therapeutic target in HD.