The degradation of α--synuclein is limited by dynein to drive the AALP pathway through HDAC6 upon paraquat exposure

Ai Qi; Kaidong Wang; Yujing Li; Rong Hu; Guiling Hu; Yang Li; Ge Shi; Min Huang

Ecotoxicology and Environmental Safety (Sep 2024)

The degradation of α--synuclein is limited by dynein to drive the AALP pathway through HDAC6 upon paraquat exposure

Ai Qi,
Kaidong Wang,
Yujing Li,
Rong Hu,
Guiling Hu,
Yang Li,
Ge Shi,
Min Huang

Affiliations

Ai Qi: 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
Kaidong Wang: 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
Yujing Li: 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
Rong Hu: 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
Guiling Hu: 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
Yang Li: 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
Ge Shi: 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; Corresponding author at: School of Public Health, Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China.
Min Huang: 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; Corresponding author at: School of Public Health, Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, China.

Journal volume & issue: Vol. 283
p. 116841

Abstract

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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.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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