Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress.
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.
Kim
Raymond H
RH
Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1.
Smith
Patrice D
PD
Aleyasin
Hossein
H
Hayley
Shawn
S
Mount
Matthew P
MP
Pownall
Scott
S
Wakeham
Andrew
A
You-Ten
Annick J
AJ
Kalia
Suneil K
SK
Horne
Patrick
P
Westaway
David
D
Lozano
Andres M
AM
Anisman
Hymie
H
Park
David S
DS
Mak
Tak W
TW
D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D003714:Denervation; D018390:Gene Targeting; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020267:MPTP Poisoning / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D015513:Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000071617:Protein Deglycase DJ-1
D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1