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.

Shared and Cell Type-Specific Mitochondrial Defects and Metabolic Adaptations in Primary Cells from PINK1-Deficient Mice

“…Importantly, UCP-2 is neuroprotective in both Drosophila and mouse models of PD [40,41]. It has recently been shown that PINK1 -/- mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine neuron loss [42], although it has not been investigated whether impaired expression of UCP-2 was involved.…”

Parkinson’s disease and enhanced inflammatory response

“…Haque et al showed that PINK1 knockout mice have increased susceptibility to the ROS-generating PD toxin MPTP. 114 This group rescued PINK1 deficient mice by overexpressing Parkin or DJ-1 suggesting PINK1 lies upstream of these factors in a common pathway. Additionally, Akundi et al showed repression of PINK1 expression results in heightened susceptibility to inflammatory response-mediated DA neuron loss.…”

The Role of Oxidative Stress in Parkinson's Disease

“…PINK-1 mutant flies share a similar phenotype as parkin mutants [152, 328], and over-expression of parkin can rescue the mitochondrial defects of PINK-1 mutant flies [152, 328, 329]. Parkin can also protect PINK1 deficient mice against MPTP [330]. Mechanistically, PINK1 and parkin work together for the selective clearance of damaged mitochondria through mitophagy [303].…”

“…Over-expression of DJ-1 and PINK1 synergistically protects SH-SY5Y cells against MPTP-induced cell death; this effect is lost in the presence of A39S mutant DJ-1 and P399L mutant PINK1 [332]. In vivo , viral vector mediated expression of DJ-1 mitigates the increased sensitivity of PINK1 deficient mice to MPTP [330]. Similarly, ubiquitous up-regulation of DJ-1 in Drosophila can ameliorate the phenotype of PINK1 deletion [333].…”