Dataset Information

Histones facilitate ?-synuclein aggregation during neuronal apoptosis.

ABSTRACT: Ample in vitro and in vivo experimental evidence supports the hypothesis that intercellular transmission of ?-synuclein (?S) is a mechanism underlying the spread of ?S pathology in Parkinson's disease and related disorders. What remains unexplained is where and how initial transmissible ?S aggregates form. In a previous study, we demonstrated that ?S aggregates rapidly form in neurons with impaired nuclear membrane integrity due to the interaction between nuclear proaggregant factor(s) and ?S and that such aggregates may serve as a source for ?S seeding. In the present study, we identify histones as a potential nuclear proaggregant factor for ?S aggregation in both apoptotic neurons and brains with ?S pathology. We further demonstrate that histone-induced aggregates contain a range of ?S oligomers, including protofibrils and mature fibrils, and that these ?S aggregates can seed additional aggregation. Importantly, we demonstrate transmissibility in mouse brains from stereotaxic injection. This study provides new clues to the mechanism underlying initial pathological aggregation of ?S in PD and related disorders, and could lead to novel diagnostic and therapeutic approaches.

SUBMITTER: Jiang P

PROVIDER: S-EPMC5350017 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Histones facilitate α-synuclein aggregation during neuronal apoptosis.

Jiang Peizhou P Gan Ming M Yen Shu-Hui SH McLean Pamela J PJ Dickson Dennis W DW

Acta neuropathologica 20161221 4

Ample in vitro and in vivo experimental evidence supports the hypothesis that intercellular transmission of α-synuclein (αS) is a mechanism underlying the spread of αS pathology in Parkinson's disease and related disorders. What remains unexplained is where and how initial transmissible αS aggregates form. In a previous study, we demonstrated that αS aggregates rapidly form in neurons with impaired nuclear membrane integrity due to the interaction between nuclear proaggregant factor(s) and αS an ...[more]

PMID: 28004278

Similar Datasets

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

Histones facilitate ?-synuclein aggregation during neuronal apoptosis.

Publications

Histones facilitate α-synuclein aggregation during neuronal apoptosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets