TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities.
TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities.
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DOI：
10.1016/j.nbd.2018.05.012
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发表时间：
2019-03
影响因子：
6.1
通讯作者：
La Spada AR
中科院分区：
文献类型：
--
作者：
Cortes CJ;La Spada AR
二十年前，蛋白质错误折叠和聚集积累作为神经退行性疾病的定义特征的认识为彻底检查中枢神经系统（CNS）中神经元和其他非神经元细胞中蛋白质质量控制的方式奠定了基础。自噬是一种细胞自我消化的途径，已经成为CNS蛋白质稳态的特别重要的途径，并且自噬失调已经被记录为阿尔茨海默病（AD）、帕金森病（PD）和亨廷顿病（HD）中神经变性的定义特征。转录因子EB（TFEB）是自噬的主要转录调节因子之一，因为它促进自噬体形成、溶酶体生物发生和溶酶体功能所需的基因的表达，并且它在CNS中高度表达。在过去的7年中，TFEB受到了相当大的关注，TFEB功能障碍与许多神经退行性疾病的发病机制有关。在这篇综述中，我们描绘了目前的理解如何TFEB失调参与神经退行性疾病，突出工作做AD，PD，HD，X连锁脊髓延髓肌萎缩症，肌萎缩侧索硬化症。由于TFEB是定义自噬激活状态的中心节点，因此理解TFEB功能障碍的基础的努力正在深入了解TFEB如何可能被靶向用于治疗应用，这可能代表了开发广泛应用于神经变性的治疗方式的令人兴奋的机会。
Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other nonneuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Transcription factor EB (TFEB) is one of the main transcriptional regulators of autophagy, as it promotes the expression of genes required for autophagosome formation, lysosome biogenesis, and lysosome function, and it is highly expressed in CNS. Over the last 7 years, TFEB has received considerable attention and TFEB dysfunction has been implicated in the pathogenesis of numerous neurodegenerative disorders. In this review, we delineate the current understanding of how TFEB dysregulation is involved in neurodegeneration, highlighting work done on AD, PD, HD, X-linked spinal & bulbar muscular atrophy, and amyotrophic lateral sclerosis. Because TFEB is a central node in defining autophagy activation status, efforts at understanding the basis for TFEB dysfunction are yielding insights into how TFEB might be targeted for therapeutic application, which may represent an exciting opportunity for the development of a treatment modality with broad application to neurodegeneration.
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影响因子：
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作者：
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