Young Mi Oh1  · Emily A. Bacallao1  · Shin‑Ae Lee1  · Jihyun Kim1  · Samuel Swinford1  · Genevieve E. Smith2  · Bryce Britt1  · Shaymaa Madbouli Abdalla1  · Seong Won Lee1

1 Department of Biomedical Sciences, Mercer University School of Medicine, Columbus, GA 31901, USA 

2 Department of Biology and Psychology, Mercer University Colleg

Abstract

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.

Keywords

Neuronal aging; Huntington’s disease; Neurodegenerative disease; Age-associated upstream regulator; MicroRNA-mediated direct neuronal conversion; Medium spiny neurons; Neurodegeneration; Patient-derived neurons

[SpringerLink]