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Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity.

ABSTRACT: The accumulation and propagation of misfolded ?-synuclein (?-Syn) is a central feature of Parkinson's disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) ?-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-?-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing ?-Syn pathology in primary neurons or after intracerebral injection into wild-type mice. Chimeric ?-Syn fibrils demonstrate enhanced or reduced pathogenicities compared with wild-type Hu- or Ms-?-Syn fibrils. Furthermore, ?-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting that transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous ?-Syn seeds and endogenous neuronal ?-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility.

SUBMITTER: Luk KC

PROVIDER: S-EPMC5087609 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity.

Luk Kelvin C KC Covell Dustin J DJ Kehm Victoria M VM Zhang Bin B Song Insung Y IY Byrne Matthew D MD Pitkin Rose M RM Decker Samantha C SC Trojanowski John Q JQ Lee Virginia M-Y VM

Cell reports 20160901 12

The accumulation and propagation of misfolded α-synuclein (α-Syn) is a central feature of Parkinson's disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) α-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-α-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology po ...[more]

PMID: 27653697

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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

Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity.

Publications

Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity.

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