Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1.

Abstract

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.

• Authors: M Emdadul Haque, Matthew P Mount, Farzaneh Safarpour, Elizabeth Abdel-Messih, Steve Callaghan, Chantal Mazerolle, Tohru Kitada, Ruth S Slack, Valerie Wallace, Jie Shen, Hymie Anisman, David S Park
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 27 Pg. 23162-70 (Jun 29 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22511790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Neurotoxins
• Oncogene Proteins
• RNA, Small Interfering
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Ubiquitin-Protein Ligases
• parkin protein
• Protein Kinases
• PTEN-induced putative kinase
• PARK7 protein, human
• Protein Deglycase DJ-1

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology)
• Adenoviridae (genetics)
• Animals
• Dopaminergic Neurons (drug effects, physiology)
• Gene Transfer Techniques
• Genes, Recessive
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• MPTP Poisoning (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nerve Degeneration (chemically induced, genetics, metabolism)
• Neurotoxins (pharmacology)
• Oncogene Proteins (genetics, metabolism)
• Protein Deglycase DJ-1
• Protein Kinases (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Stress, Physiological (physiology)
• Ubiquitin-Protein Ligases (genetics, metabolism)