通过在患者来源纹状体神经元中进行直接重编程建模发现，与年龄相关亨廷顿舞蹈症（HD）进展过程中存在自噬受损，这一成果由美国华盛顿大学医学院Andrew S. Yoo团队经过不懈努力而取得。2022年10月27日出版的《自然-神经科学》发表了这项成果。

在这项研究中，研究人员检测了纹状体中棘神经元（MSN），这些神经元是由HD患者的成纤维细胞通过重编程获得，以模拟年龄依赖性疾病的发生。研究发现，与来自年轻、症状前患者（pre-HD-MSN）的MSN和来自年龄相当健康对照个体的MSN相比，有症状HD-MSNs（HD-MSNs）的重编程MSN会显著发生选择性神经元死亡。

研究观察到HD-MSN和前HD-MSN之间染色质可及性会发生年龄相关变化，并发现了miR-29b-3p，其表达随年龄增加而上调并通过特异性靶向人STAT3 3′非翻译区来破坏自噬功能，从而诱导HD-MSN变性。减少miR-29b-3p或利用化学方法促进自噬增加了HD-MSN对神经变性的恢复力。该研究结果表明，HD中miRNA随着衰老而上调并诱导MSN变性，通过增强HD-MSN自噬是恢复神经退行的潜在方法。

据了解，HD是一种遗传性神经退行性疾病，在人成年后会表现出临床症状，但尚不清楚在由衰老诱导的HD患者中神经退行性疾病的发病机制。

附：英文原文

Title: Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy

Author: Oh, Young Mi, Lee, Seong Won, Kim, Woo Kyung, Chen, Shawei, Church, Victoria A., Cates, Kitra, Li, Tiandao, Zhang, Bo, Dolle, Roland E., Dahiya, Sonika, Pak, Stephen C., Silverman, Gary A., Perlmutter, David H., Yoo, Andrew S.

Issue&Volume: 2022-10-27

Abstract: 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.

DOI: 10.1038/s41593-022-01185-4

Source: https://www.nature.com/articles/s41593-022-01185-4