School of Public Health, Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China.
School of Public Health, Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China.
Ecotoxicol Environ Saf. 2024 Sep 15;283:116841. doi: 10.1016/j.ecoenv.2024.116841. Epub 2024 Aug 10.
Lewy body disease (LBD), one of the most common neurodegenerative diseases (NDDs), is characterized by excessive accumulation of α-synuclein (α-syn) in neurons. In recent years, environmental factors such as exposure to herbicides and pesticides have been attributed to the development of this condition. While majority of the studies on neurotoxic effects of paraquat (PQ) have focused on α-syn-mediated neuronal damage in the early stages of α-syn accumulation in neurons, efforts to explore the key target for α-syn degradation are limited. Recent research has suggested that histone deacetylase 6 (HDAC6) might possibly regulate amyloid clearance, and that the metabolism of compounds in neurons is also directly affected by axonal transport in neurons. Dynein predominantly mediates reverse transportation of metabolites and uptake of signal molecules and other compounds at the end of axons, which is conducive to the reuse of cell components. However, the role of interaction of dynein with HDAC6 in metabolites transport is still unclear. Therefore, this study aimed to investigate the role of HDAC6 in α-syn accumulation/clearance in neurons and the associated possible influencing factors. The results revealed that HDAC6 could transport ubiquitinated α-syn, bind to dynein, form an aggresome, and relocate to the center of the microtubule tissue, ultimately reducing abnormal accumulation of α-syn. However, PQ treatment resulted in HDAC6 upregulation, causing abnormal aggregation of α-syn. Taken together, these findings indicated that PQ exposure caused abnormal accumulation of α-syn and decreased effective degradation of α-syn by HDAC6-mediated aggresome-autophagy-lysosome pathway.
路易体病（LBD）是最常见的神经退行性疾病（NDDs）之一，其特征是神经元中α-突触核蛋白（α-syn）的过度积累。近年来，环境因素，如接触除草剂和杀虫剂，被认为与这种疾病的发展有关。虽然大多数关于百草枯（PQ）神经毒性作用的研究都集中在神经元中α-syn 积累早期α-syn 介导的神经元损伤上，但探索α-syn 降解的关键靶点的努力是有限的。最近的研究表明，组蛋白去乙酰化酶 6（HDAC6）可能调节淀粉样蛋白的清除，神经元中的化合物代谢也直接受到神经元轴突运输的影响。动力蛋白主要介导代谢物的反向运输以及信号分子和其他化合物在轴突末端的摄取，这有利于细胞成分的再利用。然而，动力蛋白与 HDAC6 相互作用在代谢物运输中的作用尚不清楚。因此，本研究旨在探讨 HDAC6 在神经元中α-syn 积累/清除中的作用及其相关的可能影响因素。结果表明，HDAC6 可以运输泛素化的α-syn，与动力蛋白结合，形成聚集体，并重新定位到微管组织的中心，最终减少α-syn 的异常积累。然而，PQ 处理导致 HDAC6 上调，导致α-syn 异常聚集。总之，这些发现表明，PQ 暴露导致α-syn 的异常积累，并通过 HDAC6 介导的聚集体-自噬-溶酶体途径降低α-syn 的有效降解。
