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

doi:10.1073/pnas.0501282102

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

^*Campbell Family Institute for Breast Cancer Research, Advanced Medical Discovery Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1; ^‡Neuroscience Research Group, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada K1H 8M5; ^§Institute for Neuroscience, Carleton University, Ottawa, ON, Canada K1H 6N5; ^¶enGene Incorporated, Vancouver, BC, Canada V6T 1Z3; ^∥Division of Applied and Interventional Research, Toronto Western Hospital Research Institute, Toronto, ON, Canada M5T 2S8; and ^**Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2

Contributed by Tak W. Mak, February 16, 2005

Abstract

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.

Footnotes

↵ ‡‡ To whom correspondence may be addressed. E-mail: dpark{at}uottawa.ca or tmak{at}uhnres.utoronto.ca.
↵ † R.H.K. and P.D.S. contributed equally to this work.
↵ †† D.S.P. and T.W.M. contributed equally to this work.
Author contributions: R.H.K., P.D.S., H. Aleyasin, S.H., S.P., S.K.K., D.W., A.M.L., D.S.P., and T.W.M. designed research; R.H.K., P.D.S., H. Aleyasin, S.H., M.P.M., A.W., A.J.Y.-T., and H. Anisman performed research; P.H. contributed new reagents/analytic tools; R.H.K. and D.S.P. analyzed data; and R.H.K. and D.S.P. wrote the paper.
Abbreviations: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine; MPP+, active metabolite of MPTP; PD, Parkinson's disease; SNc, substantia nigra pars compacta; TH, tyrosine hydroxylase; DAT, dopamine transporter protein.
Freely available online through the PNAS open access option.