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Propofol Attenuates ?-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke.

ABSTRACT: ?-Synuclein is a soluble monomer abundant in the central nervous system. Aggregates of ?-synuclein, consisting of higher-level oligomers and insoluble fibrils, have been observed in many chronic neurological diseases and are implicated in neurotoxicity and neurodegeneration. ?-Synuclein has recently been shown to aggregate following acute ischemic stroke, exacerbating neuronal damage. Propofol is an intravenous anesthetic that is commonly used during intravascular embolectomy following acute ischemic stroke. While propofol has demonstrated neuroprotective properties following brain injury, the mechanism of protection in the setting of ischemic stroke is unclear. In this study, propofol administration significantly reduced the neurotoxic aggregation of ?-synuclein, decreased the infarct area, and attenuated the neurological deficits after ischemic stroke in a mouse model. We then demonstrated that the propofol-induced reduction of ?-synuclein aggregation was associated with increased mammalian target of rapamycin/ribosomal protein S6 kinase beta-1 signaling pathway activity and reduction of the excessive autophagy occurring after acute ischemic stroke.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7056784 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Propofol Attenuates α-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke.

Wang Yuzhu Y Tian Dan D Wei Changwei C Cui Victoria V Wang Huan H Zhu Yanbing Y Wu Anshi A Yue Yun Y

Neuroscience bulletin 20190913 3

α-Synuclein is a soluble monomer abundant in the central nervous system. Aggregates of α-synuclein, consisting of higher-level oligomers and insoluble fibrils, have been observed in many chronic neurological diseases and are implicated in neurotoxicity and neurodegeneration. α-Synuclein has recently been shown to aggregate following acute ischemic stroke, exacerbating neuronal damage. Propofol is an intravenous anesthetic that is commonly used during intravascular embolectomy following acute isc ...[more]

PMID: 31520398

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Project description:Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH abusers are at high risk of neurodegenerative disorders, including Parkinson's disease (PD). Previous studies have demonstrated that METH causes alpha-synuclein (?-syn) aggregation in the both laboratory animal and human. In this study, exposure to high METH doses increased the expression of ?-syn and the small ubiquitin-related modifier 1 (SUMO-1). Therefore, we hypothesized that SUMOylation of ?-syn is involved in high-dose METH-induced ?-syn aggregation. We measured the levels of ?-syn SUMOylation and these enzymes involved in the SUMOylation cycle in SH-SY5Y human neuroblastoma cells (SH-SY5Y cells), in cultures of C57 BL/6 primary mouse neurons and in brain tissues of mice exposure to METH. We also demonstrated the effect of ?-syn SUMOylation on ?-syn aggregation after METH exposure by overexpressing the key enzyme of the SUMOylation cycle or silencing SUMO-1 expression in vitro. Then, we make introduced mutations in the major SUMOylation acceptor sites of ?-syn by transfecting a lentivirus containing the sequence of WT ?-syn or K96/102R ?-syn into SH-SY5Y cells and injecting an adenovirus containing the sequence of WT ?-syn or K96/102R ?-syn into the mouse striatum. Levels of the ubiquitin-proteasome system (UPS)-related makers ubiquitin (Ub) and UbE1, as well as the autophagy-lysosome pathway (ALP)-related markers LC3, P62 and lysosomal associated membrane protein 2A (LAMP2A), were also measured in SH-SY5Y cells transfected with lentivirus and mice injected with adenovirus. The results showed that METH exposure decreases the SUMOylation level of ?-syn, although the expression of ?-syn and SUMO-1 are increased. One possible cause is the reduction of UBC9 level. The increase in ?-syn SUMOylation by UBC9 overexpression relieves METH-induced ?-syn overexpression and aggregation, whereas the decrease in ?-syn SUMOylation by SUMO-1 silencing exacerbates the same pathology. Furthermore, mutations in the major SUMOylation acceptor sites of ?-syn also aggravate ?-syn overexpression and aggregation by impairing degradation through the UPS and the ALP in vitro and in vivo. These results suggest that SUMOylation of ?-syn plays a fundamental part in ?-syn overexpression and aggregation induced by METH and could be a suitable target for the treatment of neurodegenerative diseases.

Dataset Information

Propofol Attenuates ?-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke.

Publications

Propofol Attenuates α-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke.

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