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Neuroprotective effects of genistein on SH-SY5Y cells overexpressing A53T mutant ?-synuclein.

ABSTRACT: Genistein, a potent antioxidant compound, protects dopaminergic neurons in a mouse model of Parkinson's disease. However, the mechanism underlying this action remains unknown. This study investigated human SH-SY5Y cells overexpressing the A53T mutant of ?-synuclein. Four groups of cells were assayed: a control group (without any treatment), a genistein group (incubated with 20 ?M genistein), a rotenone group (treated with 50 ?M rotenone), and a rotenone + genistein group (incubated with 20 ?M genistein and then treated with 50 ?M rotenone). A lactate dehydrogenase release test confirmed the protective effect of genistein, and genistein remarkably reversed mitochondrial oxidative injury caused by rotenone. Western blot assays showed that BCL-2 and Beclin 1 levels were markedly higher in the genistein group than in the rotenone group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling revealed that genistein inhibited rotenone-induced apoptosis in SH-SY5Y cells. Compared with the control group, the expression of NFE2L2 and HMOX1 was significantly increased in the genistein + rotenone group. However, after treatment with estrogen receptor and NFE2L2 channel blockers (ICI-182780 and ML385, respectively), genistein could not elevate NFE2L2 and HMOX1 expression. ICI-182780 effectively prevented genistein-mediated phosphorylation of NFE2L2 and remarkably suppressed phosphorylation of AKT, a protein downstream of the estrogen receptor. These findings confirm that genistein has neuroprotective effects in a cell model of Parkinson's disease. Genistein can reduce oxidative stress damage and cell apoptosis by activating estrogen receptors and NFE2L2 channels.

SUBMITTER: Wu HC

PROVIDER: S-EPMC6108222 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Neuroprotective effects of genistein on SH-SY5Y cells overexpressing A53T mutant α-synuclein.

Wu Huan-Cheng HC Hu Qun-Liang QL Zhang Shi-Jun SJ Wang Yan-Min YM Jin Zhan-Kui ZK Lv Ling-Fu LF Zhang Sai S Liu Zhen-Lin ZL Wu Hong-Lian HL Cheng Ou-Mei OM

Neural regeneration research 20180801 8

Genistein, a potent antioxidant compound, protects dopaminergic neurons in a mouse model of Parkinson's disease. However, the mechanism underlying this action remains unknown. This study investigated human SH-SY5Y cells overexpressing the A53T mutant of α-synuclein. Four groups of cells were assayed: a control group (without any treatment), a genistein group (incubated with 20 μM genistein), a rotenone group (treated with 50 μM rotenone), and a rotenone + genistein group (incubated with 20 μM ge ...[more]

PMID: 30106049

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Project description:Background: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and involves deficiencies in alpha-synuclein (α-Syn) degradation. Effective therapeutic strategies for PD are urgently needed. L-asparaginase (L-ASNase) has been developed for therapeutic applications in many fields because it catalyzes the hydrolysis of asparagine and glutamine in cancer cells, which may also activate autophagy and induce the degradation of accumulated α-Syn. However, the efficacy and related mechanism of L-ASNase in PD remain poorly understood. Methods: We determined the correlation between L-ASNase and autophagic degradation of α-Syn in a cell model of PD. Mitochondrial function and apoptosis were examined in the presence or absence of L-ASNase. Then, we applied GC-MS/MS targeted amino acid metabolomics analysis to validate the amino acid regulation induced by L-ASNase treatment. Glutamine was added to verify whether the neuroprotective effect was induced by deprivation of glutamine. α-Syn-related autophagy and mitochondrial fusion/fission dynamics were detected to explore the mechanism of L-ASNase-based therapy in PD. Results: L-ASNase activated the autophagic degradation of α-Syn in a cell model of PD without cytotoxicity at specific concentrations/times. Under these conditions, L-ASNase showed substantial neuroprotective effects, including improvements in mitochondrial function and decreased apoptosis. Through GC-MS/MS targeted analysis, glutamine metabolism was identified as the target of L-ASNase in PD treatment, and the neuroprotective effect of L-ASNase was reduced after glutamine supplementation. Conclusions: Our study demonstrated for the first time that L-ASNase had a neuroprotective effect on a cell model of PD through a moderate deprivation of glutamine, which induced autophagic activation and mitochondrial fusion. Therefore, we demonstrated that L-ASNase could be a promising and effective drug for PD treatment.

Dataset Information

Neuroprotective effects of genistein on SH-SY5Y cells overexpressing A53T mutant ?-synuclein.

Publications

Neuroprotective effects of genistein on SH-SY5Y cells overexpressing A53T mutant α-synuclein.

Similar Datasets

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