title: The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration.
abstract: The etiological role of dysregulated autophagy in neurodegenerative diseases has been a subject of intense investigation. While manganese (Mn) is known to cause dopaminergic (DAergic) neurodegeneration, it has yet to be determined whether the dysregulation of autophagy plays a role in Mn-induced neuronal injury. In this study, we investigated the effect of Mn on autophagy in a rat model of manganism, a neurodegenerative disease associated with excessive exposure to Mn. After a single intrastriatal injection of Mn, the short- (4-12 h) and long-term (1-28 days) effect of Mn on DAergic neurons and autophagy were examined. Marked reduction in the number of TH-immunoreactive neurons in the substantia nigra pars compacta (SNpc) as well as TH protein expression, and a significant increase of apomorphine-induced rotations were observed in rats after Mn injection. Manganese also induced the down-regulation of dopamine levels and D1 dopamine receptor expression. In addition, autophagy was dysregulated and inhibited, as evidenced by increased number of abnormal lysosomes, decreased protein expression of Beclin1, and decreased ratio of microtubule-associated protein 1 light chain 3 (LC3) II over LC3 I, concomitant with activated mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70s6k) signaling. In contrast, in the early phase of Mn exposure, the level of autophagy was not be suppressed but compensatorily activated. Although the morphology of the DAergic neuron was intact in the early phase, Mn caused a significant decrease in TH-immunoreactivity and a significant increase in apomorphine-induced rotations in the presence of wortmannin, an inhibitor of autophagy. Taken together, these results demonstrate, for the first time, that autophagy may play a protective role against Mn-induced neuronal damage, whilst dysregulation of autophagy at later phases may mediate DAergic neurodegeneration.
authors.affiliation: Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032, China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Cao
authors.forename: Tongjian
authors.initials: T
authors.lastname: Cai
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Ting
authors.initials: T
authors.lastname: Yao
authors.forename: Yaoming
authors.initials: Y
authors.lastname: Chen
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Cao
authors.forename: Wenjing
authors.initials: W
authors.lastname: Luo
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008345:Manganese / Q000633:toxicity*; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure
chemical_list: D008345:Manganese