Modeling Huntington disease through microRNA-mediated neuronal reprogramming identifies age-associated autophagy dysfunction driving the onset of neurodegeneration.
Modeling Huntington disease through microRNA-mediated neuronal reprogramming identifies age-associated autophagy dysfunction driving the onset of neurodegeneration.
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通过 microRNA 介导的神经元重编程对亨廷顿病进行建模，识别出与年龄相关的自噬功能障碍，从而导致神经退行性变的发生。
DOI：
10.1080/15548627.2023.2175572
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发表时间：
2023
期刊：
影响因子：
13.3
通讯作者：
Yoo,AndrewS
中科院分区：
文献类型：
--
作者：
Oh,YoungMi;Lee,SeongWon;Yoo,AndrewS
亨廷顿病（Huntington disease，HD）是一种遗传性神经退行性疾病，以成人起病。然而，衰老触发HD患者神经退行性变发作的机制仍不清楚。通过直接重编程来自不同疾病阶段的HD患者的成纤维细胞产生的纹状体中型多刺神经元（MSN）对HD的年龄依赖性进展进行建模，确定了关键细胞功能的年龄依赖性下降，例如自噬/巨自噬和神经变性的发作。从机制上讲，来自有症状的HD患者的MSN（HD-MSN）的特征是与来自年轻的症状前患者的MSN相比，MIR 29 B-3 phost基因附近的染色质可接近性增加，并且其上调。MIR 29 B-3针转靶向并抑制控制自噬体生物发生的STAT 3（信号转导子和转录激活子3），导致HD-MSN变性。我们最近的研究表明年龄相关的microRNA（miRNA）和自噬失调与MSN变性有关，以及通过增强HD中的自噬来保护MSN的潜在方法。缩写：HD：亨廷顿病; mHTT：突变HTT; MIR 9/9*-124：MIR 9/9* 和MIR 124; miRNA：microRNA; MSN：中型棘神经元; STAT 3：信号转导和转录激活因子3
Huntington disease (HD) is an inherited neurodegenerative disease with adult-onset clinical symptoms. However, the mechanism by which aging triggers the onset of neurodegeneration in HD patients remains unclear. Modeling the age-dependent progression of HD with striatal medium spiny neurons (MSNs) generated by direct reprogramming of fibroblasts from HD patients at different disease stages identifies age-dependent decline in critical cellular functions such as autophagy/macroautophagy and onset of neurodegeneration. Mechanistically, MSNs derived from symptomatic HD patients (HD-MSNs) are characterized by increased chromatin accessibility proximal to theMIR29B-3phost gene and its upregulation compared to MSNs from younger pre-symptomatic patients.MIR29B-3pin turn targets and represses STAT3 (signal transducer and activator of transcription 3) that controls the biogenesis of autophagosomes, leading to HD-MSN degeneration. Our recent study demonstrates age-associated microRNA (miRNA) and autophagy dysregulation linked to MSN degeneration, and potential approaches for protecting MSNs by enhancing autophagy in HD.Abbreviations:HD: Huntington disease; mHTT: mutant HTT;MIR9/9*-124: MIR9/9* and MIR124; miRNA: microRNA; MSN: medium spiny neuron; STAT3: signal transducer and activator of transcription 3