DJ-1 and Parkin modulate dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron loss in mice.
Parkin-deficient animals exhibit mitochondrial degeneration and increased oxidative stress vulnerability, and both mice and flies lacking DJ-1 are hypersensitive to environmental toxins associated with Parkinson's disease (PD). We used recombinant adeno-associated virus (AAV) gene transfer to study the influence of DJ-1 and Parkin on the dopaminergic system of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, a model for sporadic PD. After MPTP lesioning, significantly more dopamine neurons survived in the virus-injected substantia nigra of the AAV-DJ-1 and AAV-Parkin mice when compared with AAV-enhanced green fluorescent protein injected controls. Protection at the neuronal level was supported by increased amphetamine-induced contralateral turning behavior. Normal mice expressing DJ-1 showed apomorphine-induced ipsilateral turning, suggesting a hyporesponsiveness of striatal dopamine D1 receptors in the DJ-1-expressing hemisphere. MPTP drastically reduced dopamine to 19% of normal levels and neither DJ-1 nor Parkin protected against MPTP-induced catecholamine loss under these conditions. Our results show that Parkin and DJ-1 inhibit dopamine neuron death and enhance amphetamine-induced dopaminergic function in a mouse model of idiopathic PD. However, DJ-1 overexpression also reduced postsynaptic dopamine receptor responses in normal mice. These results warrant further exploration of DJ-1 and Parkin gene therapy for PD, although a better understanding of their effects on behavior and dopamine neurotransmission is required before these proteins can be safely used.
Paterna
Jean-Charles
JC
Institute of Molecular Biology, University of Zurich, Zurich, Switzerland.
Leng
Andreas
A
Weber
Elisabeth
E
Feldon
Joram
J
Büeler
Hansruedi
H
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D000229:Dependovirus / Q000235:genetics; D004298:Dopamine / Q000502:physiology*; D015316:Genetic Therapy; D020267:MPTP Poisoning / Q000473:pathology / Q000503:physiopathology / Q000523:psychology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology / Q000502:physiology; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology
D015513:Oncogene Proteins; D000661:Amphetamine; D054464:Peroxiredoxins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D001058:Apomorphine; D004298:Dopamine