伪-Synuclein and mitochondrial bioenergetics regulate tetrahydrobiopterin levels in a human dopaminergic model of Parkinson disease
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- 作者：Brent J. Ryan ; Lara L. Louren莽o-Venda ; Mark J. Crabtree ; Ashley B. Hale ; Keith M. Channon ; Richard Wade-Martins
- 关键词：PD ; Parkinson disease ; SNPc ; substantia nigra pars compacta ; 伪-syn ; 伪-synuclein ; GTPCH ; GTP cyclohydrolase I ; MPTP ; 1-methyl-4-phenyl-1 ; 2 ; 3 ; 6-tetrahydropyridine ; MPP+ ; 1-methyl-4-phenylpyridinium ; NOS ; nitric oxide synthase ; DAT ; dopamine transporter ; BH4 ; 5 ; 6 ; 7 ; 8-tetrahydrobiopterin ; BH2 ; 7 ; 8-dihydrobiopterin ; B ; biopterin ; PI ; propidium iodide ; OCR ; oxygen consumption rate ; ECAR ; extracellular acidification rate ; GIRK2 ; G-protein-activated inward rectifier potassium channel 2
- 刊名：Free Radical Biology and Medicine
- 出版年：February, 2014
- 年：2014
- 卷：67
- 期：Complete
- 页码：58-68
- 全文大小：2203 K
文摘
Parkinson disease (PD) is a multifactorial disease resulting in preferential death of the dopaminergic neurons in the substantia nigra. Studies of PD-linked genes and toxin-induced models of PD have implicated mitochondrial dysfunction, oxidative stress, and the misfolding and aggregation of 伪-synuclein (伪-syn) as key factors in disease initiation and progression. Many of these features of PD may be modeled in cells or animal models using the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Reducing oxidative stress and nitric oxide synthase (NOS) activity has been shown to be protective in cell or animal models of MPP+ toxicity. We have previously demonstrated that siRNA-mediated knockdown of 伪-syn lowers the activity of both dopamine transporter and NOS activity and protects dopaminergic neuron-like cells from MPP+ toxicity. Here, we demonstrate that 伪-syn knockdown and modulators of oxidative stress/NOS activation protect cells from MPP+-induced toxicity via postmitochondrial mechanisms rather than by a rescue of the decrease in mitochondrial oxidative phosphorylation caused by MPP+ exposure. We demonstrate that MPP+ significantly decreases the synthesis of the antioxidant and obligate cofactor of NOS and TH tetrahydrobiopterin (BH4) through decreased cellular GTP/ATP levels. Furthermore, we demonstrate that RNAi knockdown of 伪-syn results in a nearly twofold increase in GTP cyclohydrolase I activity and a concomitant increase in basal BH4 levels. Together, these results demonstrate that both mitochondrial activity and 伪-syn play roles in modulating cellular BH4 levels.