Dataset Information

Aggregation of ?-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis.

ABSTRACT: Parkinson's disease is the most common neurodegenerative movement disorder. ?-Synuclein is a small synaptic protein that has been linked to familial Parkinson's disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of ?-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of ?-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of ?-synuclein toxicity, but the exact role ?-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that ?-synuclein induces aggregation of many yeast Rab GTPase proteins, that ?-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that ?-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that ?-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome-Golgi transport, linking a specific trafficking defect to ?-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for ?-synuclein neurotoxicity.

SUBMITTER: Soper JH

PROVIDER: S-EPMC3147281 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aggregation of α-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis.

Soper James H JH Kehm Victoria V Burd Christopher G CG Bankaitis Vytas A VA Lee Virginia M-Y VM

Journal of molecular neuroscience : MN 20101002 3

Parkinson's disease is the most common neurodegenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson's disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was sho ...[more]

PMID: 20890676

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

Aggregation of ?-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis.

Publications

Aggregation of α-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets