期刊
NEUROBIOLOGY OF DISEASE
卷 81, 期 -, 页码 76-92出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.11.018
关键词
alpha-Synuclein; A53T; Autophagy; Proteasome; Ubiquitination; Oxidative stress; AMPK; Copper and Parkinson's disease
资金
- National Institutes of Health [P20RR17675]
- Branfman Family Foundation [ES016337 GM108975, NSO49221, NS058395-04]
- Alzheimer's Association [NIRGD-10-172826]
- National Council of Science and Technology (CONACYT) of Mexico [211456]
- NIGMS [P30 GM103509]
Gene multiplications or point mutations in alpha (alpha)-synuclein are associated with familial and sporadic Parkinson's disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which alpha-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of wild type (WT) or mutant A53T alpha-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu-induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, alpha-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T alpha-synuclein overexpression exacerbated Cu toxicity in dopaminergic and yeast cells in the absence of alpha-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and alpha-synuclein overexpression. Our results demonstrate that alpha-synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways. (C) 2014 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据