Histone deacetylase 6 and aggresome-associated neurodegeneration

描述（由申请人提供）：蛋白质聚集体的积累和线粒体功能受损已成为神经退行性疾病的共同特征。本申请的长期目标是阐明识别和处理毒性实体的关键细胞机制及其在神经退行性疾病发病机制中的重要性。我们已经发现，泛素结合脱乙酰酶HDAC6是路易体的一个组成部分，并在蛋白质聚集体和受损线粒体的清除中发挥关键作用。在小鼠中，HDAC6的缺失导致蛋白质聚集体的积累和神经变性。我们已经确定HDAC6是质量控制（QC）自噬的关键组成部分，最近已成为负责消除蛋白质聚集体和受损线粒体的关键机制。我们发现QC自噬在功能上和分子上与饥饿诱导的自噬不同，这表明了一种新的机制，用于处理与神经变性相关的毒性实体。在本申请中，我们提出阐明HDAC6控制和连接侵袭体途径和QC自噬的分子机制，从而促进有毒蛋白聚集体的清除。通过描述QC自噬的分子组成和调控，我们希望获得细胞如何处理和处置有毒蛋白质聚集体以及神经退行性疾病进展的机制基础的新见解。

DESCRIPTION (provided by applicant): The accumulation of protein aggregates and impaired mitochondrial function has emerged as a common denominator in neurodegenerative diseases. The long-term objective of this application is to elucidate the cellular machinery critical for the recognition and processing of toxic entities and its importance in the pathogenesis of neurodegenerative disease. We have discovered that the ubiquitin-binding deacetylase HDAC6 is a component of Lewy bodies and plays a critical role in the clearance of protein aggregate and impaired mitochondria. In mice, loss of HDAC6 results in accumulation of protein aggregates and neurodegeneration. We have identified HDAC6 as a critical component of quality control (QC) autophagy, which has recently emerged as the key machinery responsible for eliminating protein aggregates and damaged mitochondrial. We found that QC autophagy is functionally and molecularly distinct from the well characterized starvation-induced autophagy, suggesting a novel mechanism for the disposal of toxic entities linked to neurodegeneration. In this application, we propose to elucidate the molecular mechanism by which HDAC6 controls and connects the aggresomal pathway and QC autophagy, thereby facilitating the clearance of toxic protein aggregates. By delineating the molecular composition and regulation of QC autophagy, we wish to gain novel insight into how cells process and dispose toxic protein aggregates and the mechanistic basis for the progression of neurodegenerative disease.