title: Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity.
abstract: Oxidative stress is implicated in the death of dopaminergic neurons in sporadic forms of Parkinson's disease. Because oxidative stress can be modulated endogenously by uncoupling proteins (UCPs), we hypothesized that specific neuronal expression of UCP2, one member of the UCP family that is rapidly induced in the CNS following insults, could confer neuroprotection in a mouse model of Parkinson's disease. We generated transgenic mice overexpressing UCP2 in catecholaminergic neurons under the control of the tyrosine hydroxylase promoter (TH-UCP2). In these mice, dopaminergic neurons of the substantia nigra showed a twofold elevation in UCP2 expression, elevated uncoupling of their mitochondria, and a marked reduction in indicators of oxidative stress, an effect also observed in the striatum. Upon acute exposure to 1,2,3,6-methyl-phenyl-tetrahydropyridine, TH-UCP2 mice showed neuroprotection and retention of locomotor functions. Our data suggest that UCP2 may represent a drug target for slowing the progression of Parkinson's disease.
authors.affiliation: Harold L. Dorris Neurological Research Center, Scripps Research Institute, La Jolla, California 92037, USA. bconti@scripps.edu
authors.forename: Bruno
authors.initials: B
authors.lastname: Conti
authors.forename: Shuei
authors.initials: S
authors.lastname: Sugama
authors.forename: Jacinta
authors.initials: J
authors.lastname: Lucero
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Winsky-Sommerer
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Wirz
authors.forename: Pamela
authors.initials: P
authors.lastname: Maher
authors.forename: Zane
authors.initials: Z
authors.lastname: Andrews
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Barr
authors.forename: Maria C
authors.initials: MC
authors.lastname: Morale
authors.forename: Covadonga
authors.initials: C
authors.lastname: Paneda
authors.forename: Janell
authors.initials: J
authors.lastname: Pemberton
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gaidarova
authors.forename: M Margarita
authors.initials: MM
authors.lastname: Behrens
authors.forename: Flint
authors.initials: F
authors.lastname: Beal
authors.forename: Pietro Paolo
authors.initials: PP
authors.lastname: Sanna
authors.forename: Tamas
authors.initials: T
authors.lastname: Horvath
authors.forename: Tamas
authors.initials: T
authors.lastname: Bartfai
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D007473:Ion Channels; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics; D000071246:Uncoupling Protein 2; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine