Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 27, Pages 23162-23170Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.346437
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Funding
- Neuroscience Canada
- Canadian Institute of Health Research
- Centre for Stroke Recovery
- Parkinson's Disease Foundation
- Parkinson's Society Canada
- Parkinson's Research Consortium
- Centres of Excellence in Neurodegeneration (COEN)
- National Research Foundation of Korea
- Ministry of Education, Science and Technology, South Korea [R31-2008-000-20004-0]
- Heart and Stroke Foundation Ontario
- Heart and Stroke Foundation, Ontario
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Mutations in the mitochondrial PTEN-induced kinase 1 (Pink1) gene have been linked to Parkinson disease (PD). Recent reports including our own indicated that ectopic Pink1 expression is protective against toxic insult in vitro, suggesting a potential role for endogenous Pink1 in mediating survival. However, the role of endogenous Pink1 in survival, particularly in vivo, is unclear. To address this critical question, we examined whether down-regulation of Pink1 affects dopaminergic neuron loss following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the adult mouse. Two model systems were utilized: virally delivered shRNA-mediated knockdown of Pink1 and germ line-deficient mice. In both instances, loss of Pink1 generated significant sensitivity to damage induced by systemic MPTP treatment. This sensitivity was associated with greater loss of dopaminergic neurons in the Substantia Nigra pars compacta and terminal dopamine fiber density in the striatum region. Importantly, we also show that viral mediated expression of two other recessive PD-linked familial genes, DJ-1 and Parkin, can protect dopaminergic neurons even in the absence of Pink1. This evidence not only provides strong evidence for the role of endogenous Pink1 in neuronal survival, but also supports a role of DJ-1 and Parkin acting parallel or downstream of endogenous Pink1 to mediate survival in a mammalian in vivo context.
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