Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity.
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.
Conti
Bruno
B
Harold L. Dorris Neurological Research Center, Scripps Research Institute, La Jolla, California 92037, USA. bconti@scripps.edu
Sugama
Shuei
S
Lucero
Jacinta
J
Winsky-Sommerer
Raphaelle
R
Wirz
Sebastian A
SA
Maher
Pamela
P
Andrews
Zane
Z
Barr
Alasdair M
AM
Morale
Maria C
MC
Paneda
Covadonga
C
Pemberton
Janell
J
Gaidarova
Svetlana
S
Behrens
M Margarita
MM
Beal
Flint
F
Sanna
Pietro Paolo
PP
Horvath
Tamas
T
Bartfai
Tamas
T
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
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