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SUMOylation and ubiquitination reciprocally regulate ?-synuclein degradation and pathological aggregation.

ABSTRACT: ?-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated ?-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates ?-synuclein degradation. We report that PIAS2 promotes SUMOylation of ?-synuclein, leading to a decrease in ?-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in ?-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases ?-synuclein levels by relieving the inhibition exerted on ?-synuclein proteasomal degradation. ?-Synuclein disease mutants are more SUMOylated compared with the wild-type protein, and this is associated with increased aggregation and inclusion formation. We detected a marked increase in PIAS2 expression along with SUMOylated ?-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of ?-synuclein SUMOylation in the disease. We also found a significant proportion of Lewy bodies in nigral neurons containing SUMO1 and PIAS2. Our observations suggest that SUMOylation of ?-synuclein by PIAS2 promotes ?-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on ?-synuclein. Second, SUMOylation facilitates ?-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of ?-synuclein SUMOylation provide a strategy to reduce ?-synuclein levels and possibly aggregation in PD.

SUBMITTER: Rott R

PROVIDER: S-EPMC5740625 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation.

Rott Ruth R Szargel Raymonde R Shani Vered V Hamza Haya H Savyon Mor M Abd Elghani Fatimah F Bandopadhyay Rina R Engelender Simone S

Proceedings of the National Academy of Sciences of the United States of America 20171127 50

α-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated α-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates α-synuclein degradation. We report that PIAS2 promotes SUMOylation of α-synuclein, leading to a decrease in α-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggr ...[more]

PMID: 29180403

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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 (α-syn) aggregation in the both laboratory animal and human. In this study, exposure to high METH doses increased the expression of α-syn and the small ubiquitin-related modifier 1 (SUMO-1). Therefore, we hypothesized that SUMOylation of α-syn is involved in high-dose METH-induced α-syn aggregation. We measured the levels of α-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 α-syn SUMOylation on α-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 α-syn by transfecting a lentivirus containing the sequence of WT α-syn or K96/102R α-syn into SH-SY5Y cells and injecting an adenovirus containing the sequence of WT α-syn or K96/102R α-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 α-syn, although the expression of α-syn and SUMO-1 are increased. One possible cause is the reduction of UBC9 level. The increase in α-syn SUMOylation by UBC9 overexpression relieves METH-induced α-syn overexpression and aggregation, whereas the decrease in α-syn SUMOylation by SUMO-1 silencing exacerbates the same pathology. Furthermore, mutations in the major SUMOylation acceptor sites of α-syn also aggravate α-syn overexpression and aggregation by impairing degradation through the UPS and the ALP in vitro and in vivo. These results suggest that SUMOylation of α-syn plays a fundamental part in α-syn overexpression and aggregation induced by METH and could be a suitable target for the treatment of neurodegenerative diseases.

Dataset Information

SUMOylation and ubiquitination reciprocally regulate ?-synuclein degradation and pathological aggregation.

Publications

SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation.

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