Oxidative stress involvement in manganese-induced alpha-synuclein oligomerization in organotypic brain slice cultures.
Overexposure to manganese (Mn) has been known to induce neuronal damage. However, little is known of the role that reactive oxygen species (ROS) play in protein aggregation resulting from Mn exposure. The current study investigated whether oxidative stress is involved in manganese-induced alpha-synuclein oligomerization in organotypic brain slices. After application of Mn (0-400μM) for 24h, there was a dose-dependent increase in average percentage of propidium iodide positive (PI(+)) nuclei in slices and levels of lactate dehydrogenase (LDH) in the culture medium. Moreover, the treatment with Mn resulted in a dose-dependent increase in neurocyte apoptosis, ROS level, and decrease in superoxide dismutase (SOD) activity. Mn also caused oxidative damage in cell lipid and protein. At the same time, the exposure of Mn leaded to significantly increase in the expression of alpha-synuclein mRNA and protein. Alpha-synuclein oligomerization occurred in Mn-treated slices, especially on membrane-bound form. It indicated that alpha-synuclein oligomers were more likely to combination cell membranes and resulting in membrane damage. Mn-induced neurocyte damage and alpha-synuclein oligomerization were also partially alleviated by the pretreatment with GSH and aggravated by H2O2 pretreatment. The findings revealed Mn might exert its neurotoxic effects by oxidative stress-mediated alpha-synuclein oligomerization in organotypic brain slices.
Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning 110001, People's Republic of China. xubin@mail.cmu.edu.cn
Bin
B
Xu
Sheng-Wen
SW
Wu
Chun-Wei
CW
Lu
Yu
Y
Deng
Wei
W
Liu
Yan-Gang
YG
Wei
Tian-Yao
TY
Yang
Zhao-Fa
ZF
Xu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008345:Manganese / Q000633:toxicity*; D020149:Manganese Poisoning / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology*; D050050:Protein Carbonylation / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D051844:alpha-Synuclein; D008345:Manganese; D012313:RNA; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D005978:Glutathione