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L-Asparaginase Exerts Neuroprotective Effects in an SH-SY5Y-A53T Model of Parkinson's Disease by Regulating Glutamine Metabolism.

ABSTRACT: Background: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and involves deficiencies in alpha-synuclein (?-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 ?-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 ?-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. ?-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 ?-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.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC7557534 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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L-Asparaginase Exerts Neuroprotective Effects in an SH-SY5Y-A53T Model of Parkinson's Disease by Regulating Glutamine Metabolism.

Zhang Qingxi Q Gao Yuyuan Y Zhang Jiahui J Li You Y Chen Jianing J Huang Rui R Ma Guixian G Wang Limin L Zhang Yuhu Y Nie Kun K Wang Lijuan L

Frontiers in molecular neuroscience 20200930

<b>Background</b>: 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 e ...[more]

PMID: 33117129

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Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear cause. It appears that multiple factors participate in the process of neuronal damage including oxidative stress and accumulation of the protein amyloid ? (A?) in the brain. The search for a treatment for this disorder is essential as current medications are limited to alleviating symptoms and palliative effects. The aim of this study is to investigate the effects of mint extracts on selected mechanisms implicated in the development of AD. To enable a thorough investigation of mechanisms, including effects on ?-secretase (the enzyme that leads to the formation of A?), on A? aggregation, and on oxidative stress and apoptosis pathways, a neuronal cell model, SH-SY5Y cells, was selected. Six Mentha taxa were investigated for their in vitro ?-secretase (BACE) and A?-aggregation inhibition activities. Moreover, their neuroprotective effects on H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells were evaluated through caspase activity. Real-time PCR and Western blot analysis were carried out for the two most promising extracts to determine their effects on signalling pathways in SH-SY5Y cells. All mint extracts had strong BACE inhibition activity. M. requienii extracts showed excellent inhibition of A?-aggregation, while other extracts showed moderate inhibition. M. diemenica and M. requienii extracts lowered caspase activity. Exposure of SH-SY5Y cells to M. diemenica extracts resulted in a decrease in the expression of pro-apoptotic protein, Bax, and an elevation in the anti-apoptotic protein, Bcl-xL, potentially mediated by down-regulation of the ASK1-JNK pathway. These results indicate that mint extracts could prevent the formation of A? and also could prevent their aggregation if they had already formed. M. diemenica and M. requienii extracts have potential to suppress apoptosis at the cellular level. Hence, mint extracts could provide a source of efficacious compounds for a therapeutic approach for AD.

Dataset Information

L-Asparaginase Exerts Neuroprotective Effects in an SH-SY5Y-A53T Model of Parkinson's Disease by Regulating Glutamine Metabolism.

Publications

L-Asparaginase Exerts Neuroprotective Effects in an SH-SY5Y-A53T Model of Parkinson's Disease by Regulating Glutamine Metabolism.

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