title: α-Synuclein and mitochondrial bioenergetics regulate tetrahydrobiopterin levels in a human dopaminergic model of Parkinson disease.
abstract: 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 α-synuclein (α-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 α-syn lowers the activity of both dopamine transporter and NOS activity and protects dopaminergic neuron-like cells from MPP(+) toxicity. Here, we demonstrate that α-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 α-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 α-syn play roles in modulating cellular BH4 levels.
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Ryan
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
authors.forename: Lara L
authors.initials: LL
authors.lastname: Lourenço-Venda
authors.affiliation: British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Crabtree
authors.affiliation: British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Hale
authors.affiliation: British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK. Electronic address: richard.wade-martins@dpag.ox.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D010085:Oxidative Phosphorylation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D001708:Biopterins; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D006136:GTP Cyclohydrolase; C003402:sapropterin; D015655:1-Methyl-4-phenylpyridinium
keywords: Bioenergetics; DAT; Free radicals; GTPCH; MPP(+); Parkinson disease; Tetrahydrobiopterin; α-Synuclein