神经退行性变
自噬
下调和上调
中棘神经元
神经科学
亨廷顿病
疾病
医学
生物
内科学
基底神经节
中枢神经系统
细胞凋亡
遗传学
基因
作者
Young Mi Oh,Seong Won Lee,Woo Kyung Kim,Shawei Chen,Victoria A. Church,K. Lynn Cates,Tiandao Li,Bo Zhang,Roland E. Dolle,Sonika Dahiya,Stephen C. Pak,Gary A. Silverman,David H. Perlmutter,Andrew S. Yoo
标识
DOI:10.1038/s41593-022-01185-4
摘要
Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals. We observed age-associated alterations in chromatin accessibility between HD-MSNs and pre-HD-MSNs and identified miR-29b-3p, whose age-associated upregulation promotes HD-MSN degeneration by impairing autophagic function through human-specific targeting of the STAT3 3' untranslated region. Reducing miR-29b-3p or chemically promoting autophagy increased the resilience of HD-MSNs against neurodegeneration. Our results demonstrate miRNA upregulation with aging in HD as a detrimental process driving MSN degeneration and potential approaches for enhancing autophagy and resilience of HD-MSNs.
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