[Dual effects of different concentrations of alpha-synuclein on the neurotoxicity of 6-hydroxydopamine in SH-SY5Y cells].
α-synuclein (α-SN) has been postulated to play a pivotal role in the pathogenesis of Parkinson's disease (PD). However, the physiological functions of α-SN and the molecular and cellular mechanisms underlying neuronal loss remain unclear. Recent studies suggest that α-SN plays dual roles of neuroprotection and neurotoxicity depending on its concentration or level of expression. In the present study, we explored the potential mechanisms for α-SN to regulate neuronal survival. α-SN at different concentrations (0.1 to 40 mumol/L) with or without 50 mumol/L 6-hydroxydopamine (6-OHDA) were added into the culture medium of the SH-SY5Y dopaminergic neural cells. The cell viability was measured on post-treatment day 1, 2 and 3. The activity of proteasome inhibited by α-SN was tested by a proteasome activity assay system after 2 h of α-SN treatment. According to the activity of proteasome inhibited by α-SN, the correlative dose of proteasome inhibitor--lactacystin (10 nmol/L to 5 mumol/L) with or without 50 mumol/L 6-OHDA were used and the cell viability was assayed on post-treatment day 1, 2 and 3. The results showed that α-SN played dual roles of neuroprotection and neurotoxicity depending on its concentration. At low concentration (0.1 to 5 mumol/L), α-SN promoted the proliferation and protected neurons against the neurotoxicity of 6-OHDA; in contrast, at high concentration (10 to 40 mumol/L), α-SN possessed cytotoxicity. The results of lactacystin treatment implied that the dual roles of α-SN were related to the moderate and strong inhibition of proteasome activity. The MEK1/2 specific inhibitor PD98059 completely blocked the protection of both α-SN and lactacystin, suggesting that MAPK pathway might be involved in the neuroprotection of α-SN.
Zhou
Ming
M
Department of Neurobiology, Institute of Geriatrics of Beijing, Xuanwu Hospital of the Capital University of Medical Sciences, Key Laboratory for Neurodegenerative Disease of Ministry of Education, China.
Xu
Sheng-Li
SL
Chen
Biao
B
D000111:Acetylcysteine / Q000031:analogs & derivatives; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000009:adverse effects; D016627:Oxidopamine / Q000009:adverse effects*; D010300:Parkinson Disease; D051844:alpha-Synuclein / Q000009:adverse effects / Q000494:pharmacology*
D018696:Neuroprotective Agents; D009498:Neurotoxins; D051844:alpha-Synuclein; C067713:lactacystin; D016627:Oxidopamine; D000111:Acetylcysteine