Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress

被引:543
作者
Kim, RH
Smith, PD
Aleyasin, H
Hayley, S
Mount, MP
Pownall, S
Wakeham, A
You-Ten, AJ
Kalia, SK
Horne, P
Westaway, D
Lozano, AM
Anisman, H
Park, DS [1 ]
Mak, TW
机构
[1] Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada
[2] Univ Toronto, Campbell Fam Inst Breast Canc Res, Adv Med Discovery Inst, Ontario Canc Inst, Toronto, ON M5G 2C1, Canada
[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C1, Canada
[4] Univ Ottawa, Neurosci Res Grp, Ottawa Hlth Res Inst, Ottawa, ON K1H 8M5, Canada
[5] Carleton Univ, Inst Neurosci, Ottawa, ON K1H 6N5, Canada
[6] EnGene Inc, Vancouver, BC V6T 1Z3, Canada
[7] Toronto Western Hosp, Res Inst, Div Appl & Intervent Res, Toronto, ON M5T 2S8, Canada
[8] Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada
关键词
D O I
10.1073/pnas.0501282102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1-/- mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1-/- embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1-/- mice or cells. via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.
引用
收藏
页码:5215 / 5220
页数:6
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