Histone deacetylase 6 and aggresome-associated neurodegeneration

组蛋白脱乙酰酶 6 和攻击体相关的神经变性

• 批准号: 8417683
• 负责人: TSO-PANG YAO
• 金额: $ 33.14万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-04 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417683
• 关键词: Actins; Autophagocytosis; Autophagosome; Binding; Biochemical; Cell physiology; Cells; Code; Complex; Deacetylase; Dependence; Disease; Disease model; Endocytic Vesicle; F-Actin; G Actin; HDAC6 gene; Lesion; Lewy Bodies; Link; Lysosomes; Mediating; Mitochondria; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway interactions; Phosphotransferases; Play; Population; Process; Property; Proteins; Quality Control; Raptors; Reading; Regulation; Regulatory Element; Role; Route; Signal Pathway; Signaling Molecule; Sirolimus; Starvation; TSG101 gene; Testing; To specify; Toxic effect; Ubiquitin; Ubiquitination; Viral; Work; base; histone deacetylase 6; human FRAP1 protein; insight; neuron loss; novel; novel therapeutic intervention; particle; protein aggregate; public health relevance; secretion process; transmission process

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.

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点。该应用的长期目标是阐明对有毒实体的识别和处理至关重要的细胞机制及其在神经退行性疾病发病机制中的重要性。我们发现泛素结合脱乙酰酶 HDAC6 是路易体的一个组成部分，在蛋白质聚集体和受损线粒体的清除中发挥着关键作用。在小鼠中，HDAC6 的缺失会导致蛋白质聚集体的积累和神经退行性变。我们已经确定 HDAC6 是质量控制 (QC) 自噬的关键组成部分，它最近已成为负责消除蛋白质聚集和受损线粒体的关键机制。我们发现QC自噬在功能和分子上与充分表征的饥饿诱导的自噬不同，这表明了一种处理与神经退行性变相关的有毒实体的新机制。在本申请中，我们建议阐明HDAC6控制和连接攻击体途径和QC自噬的分子机制，从而促进有毒蛋白质聚集体的清除。通过描述 QC 自噬的分子组成和调节，我们希望获得关于细胞如何处理和处理有毒蛋白聚集体以及神经退行性疾病进展的机制基础的新见解。