Department of Biology, Molecular Neurobiology, University of Oldenburg, POB 2503, 26111, Oldenburg, Germany,
Acta Neuropathol. 2013 Dec;126(6):793-807. doi: 10.1007/s00401-013-1158-x. Epub 2013 Aug 3.
The failure to clear misfolded or aggregated proteins from the cytoplasm of nerve cells and glia is a common pathogenic event in a variety of neurodegenerative disorders. This might be causally related to defects in the major proteolytic systems, i.e., the ubiquitin-proteasomal system and the autophagic pathway. Large protein aggregates and defective organelles are excluded from the proteasome. They can be degraded only by macroautophagy, which is a highly selective process. It requires p62 to act as a bridge connecting ubiquitinated protein aggregates and autophagosomes, and the tubulin deacetylase histone deacetylase 6 (HDAC6). HDAC6 has recently been identified as a constituent in Lewy bodies of Parkinson disease and glial cytoplasmic inclusions of multiple system atrophy. It is considered a sensor of proteasomal inhibition and a cellular stress surveillance factor, and plays a central role in autophagy by controlling the fusion process of autophagosomes with lysosomes. Upon proteasomal inhibition, HDAC6 is relocated and recruited to polyubiquitin-positive aggresomes. Tubulin acetylation is a major consequence of HDAC6 inhibition, and HDAC6 inhibition restores microtubule (MT)-dependent transport mechanisms in neurons. This suggests the involvement of HDAC6 in neurodegenerative diseases. Furthermore, the protein tau seems to be a substrate for HDAC6. Tau acetylation impairs MT assembly and promotes tau fibrillization in vitro. It has been suggested that acetylation and phosphorylation of tau at multiples sites may act synergistically in the pathogenesis of tau fibrillization. In this review, we will survey the process of aggresome formation, macroautophagy and the role of autophagosomal proteins and HDAC6 in inclusion body formation.
细胞质中错误折叠或聚集的蛋白质如果不能被清除，是多种神经退行性疾病的共同致病事件。这可能与主要蛋白水解系统（即泛素-蛋白酶体系统和自噬途径）的缺陷有关。大的蛋白质聚集体和有缺陷的细胞器不能被蛋白酶体所清除。只有通过巨自噬（一种高度选择性的过程）才能将它们降解，巨自噬需要 p62 作为连接泛素化蛋白聚集体和自噬体的桥梁，以及微管去乙酰化酶组蛋白去乙酰化酶 6（HDAC6）。HDAC6 最近被鉴定为帕金森病路易体和多系统萎缩胶质细胞质包涵体的组成部分。它被认为是蛋白酶体抑制的传感器和细胞应激监测因子，通过控制自噬体与溶酶体的融合过程，在自噬中发挥核心作用。蛋白酶体抑制后，HDAC6 被重新定位并募集到多泛素阳性的聚集物中。HDAC6 抑制的一个主要后果是微管蛋白乙酰化，HDAC6 抑制恢复神经元中微管（MT）依赖性运输机制。这表明 HDAC6 参与神经退行性疾病。此外，蛋白质 tau 似乎是 HDAC6 的底物。tau 乙酰化会损害 MT 组装，并促进 tau 在体外的纤维形成。有人认为 tau 在多个位点的乙酰化和磷酸化可能在 tau 纤维形成的发病机制中协同作用。在这篇综述中，我们将调查聚集物形成、巨自噬以及自噬体蛋白和 HDAC6 在包涵体形成中的作用。
