NCEH-1 modulates cholesterol metabolism and protects against α-synuclein toxicity in a C. elegans model of Parkinson's disease.
NCEH-1 modulates cholesterol metabolism and protects against α-synuclein toxicity in a C. elegans model of Parkinson's disease.
复制标题
NCEH-1 在帕金森病的秀丽隐杆线虫模型中调节胆固醇代谢并防止 α-突触核蛋白毒性。
DOI：
10.1093/hmg/ddx269
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发表时间：
2017
影响因子：
3.5
通讯作者：
Caldwell,GuyA
中科院分区：
文献类型：
--
作者：
Zhang,Siyuan;Glukhova,SamanthaA;Caldwell,KimA;Caldwell,GuyA
帕金森病（PD）是一种与衰老相关的神经退行性疾病，影响着全球数百万人。人α-突触核蛋白的错误折叠、寡聚化和积聚是PD的关键病理学标志，并且与衰老过程中多巴胺能神经元的进行性丧失相关。通过抑制IGF-1/胰岛素样信号传导（IIS）延长寿命提供了一种可能性，通过诱导提供神经保护的代谢变化来延缓疾病发作。秀丽隐杆线虫（Caecillushabditis elegansen）的h-1基因编码中性胆固醇酯水解酶1（NCEH-1）的直向同源物，NCEH-1是IIS的下游蛋白，在筛选中被鉴定为体内α-突触核蛋白积累的调节剂。胆固醇代谢在功能上影响α-突触核蛋白诱导的神经变性的机制尚不明确。在此，我们报道了NCEH-1对C. elegansvia机制that is independent独立of lifetime寿命extension延长.我们发现胆固醇的存在、LDL受体介导的胆固醇内吞作用和胆固醇流出对NCEH-1介导的神经保护作用都是必不可少的。在保护免受α-突触核蛋白神经毒性方面，NCEH-1还刺激胆固醇衍生的神经类固醇形成并降低线粒体中的细胞活性氧。总的来说，这项研究增加了我们对胆固醇代谢如何调节神经保护机制的理解，这种机制可以减弱α-突触核蛋白的神经毒性，从而指出调节神经元胆固醇周转作为PD的潜在治疗途径。
Parkinson’s disease (PD) is an aging-associated neurodegenerative disease affecting millions worldwide. Misfolding, oligomerization and accumulation of the human α-synuclein protein is a key pathological hallmark of PD and is associated with the progressive loss of dopaminergic neurons over the course of aging. Lifespan extension via the suppression of IGF-1/insulin-like signaling (IIS) offers a possibility to retard disease onset through induction of metabolic changes that provide neuroprotection. Thenceh-1gene ofCaenorhabditis elegansencodes an ortholog of neutral cholesterol ester hydrolase 1 (NCEH-1), an IIS downstream protein that was identified in a screen as a modulator of α-synuclein accumulationin vivo. The mechanism whereby cholesterol metabolism functionally impacts neurodegeneration induced by α-synuclein is undefined. Here we report that NCEH-1 protects dopaminergic neurons from α-synuclein-dependent neurotoxicity inC. elegansvia a mechanism that is independent of lifespan extension. We discovered that the presence of cholesterol, LDLR-mediated cholesterol endocytosis, and cholesterol efflux are all essential to NCEH-1-mediated neuroprotection. In protecting from α-synuclein neurotoxicity, NCEH-1 also stimulates cholesterol-derived neurosteroid formation and lowers cellular reactive oxygen species in mitochondria. Collectively, this study augments our understanding of how cholesterol metabolism can modulate a neuroprotective mechanism that attenuates α-synuclein neurotoxicity, thereby pointing toward regulation of neuronal cholesterol turnover as a potential therapeutic avenue for PD.