title: 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.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: M Emdadul
authors.initials: ME
authors.lastname: Haque
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Mount
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Safarpour
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Abdel-Messih
authors.forename: Steve
authors.initials: S
authors.lastname: Callaghan
authors.forename: Chantal
authors.initials: C
authors.lastname: Mazerolle
authors.forename: Tohru
authors.initials: T
authors.lastname: Kitada
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.forename: Valerie
authors.initials: V
authors.lastname: Wallace
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Hymie
authors.initials: H
authors.lastname: Anisman
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D018014:Gene Transfer Techniques; D005808:Genes, Recessive; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D020267:MPTP Poisoning / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013312:Stress, Physiological / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D047908:Intracellular Signaling Peptides and Proteins; D009498:Neurotoxins; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C105131:PARK7 protein, human