Impairment of redox state and dopamine level induced by alpha-synuclein aggregation and the prevention effect of hsp70.
One hypothesis for the etiology of Parkinson's disease (PD) is that the formation of proteinaceous inclusion, which is mainly composed of alpha-synuclein, may contribute to the selective loss of dopaminergic neurons. To further explore the role of alpha-synuclein in neurodegeneration of PD, we examined the possible effects of aggregated alpha-synuclein on the intracellular redox state, dopamine level, and cell death of SK-N-SH cells. Our present studies show that alpha-synuclein aggregation gives rise to both elevated intracellular oxidative state and dopamine level in SK-N-SH cells. Moreover, alpha-synuclein aggregation results in a higher ratio of apoptosis population (55.8%+/-SEM) in cells overexpressing alpha-synuclein aggregation, compared to their normal control groups (8.0%+/-SEM). In contrast, coexpression of hsp70 with alpha-synuclein suppresses the oxidative state shift, restores the normal dopamine levels and blocks neuron cell loss. Therefore, our data provided one possible mechanism by which the alpha-synuclein aggregation may lead to the neurodegeneration in PD via regulating the level of cytoplasmic dopamine and then disturbing the intracellular redox homeostasis. On the other hand, hsp70 can mitigate the degenerative effect conferred by alpha-synuclein, acting as a protective factor in treatment of PD.
Yu
FuRong
F
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, People's Republic of China.
Xu
HuaTai
H
Zhuo
Ming
M
Sun
LanYing
L
Dong
AiWen
A
Liu
XinYuan
X
D017209:Apoptosis; D045744:Cell Line, Tumor; D004298:Dopamine / Q000096:biosynthesis*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction; D051843:Synucleins; D051844:alpha-Synuclein
D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D004298:Dopamine