Abstract
BackgroundPTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1−/− mice.Methods and FindingsPurified brain mitochondria of Pink1−/− mice showed impaired Ca2+ storage capacity, resulting in increased Ca2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1−/− mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1−/− mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1−/− mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1−/− embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1−/− mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting.ConclusionsIncreased mitochondrial Ca2+ sensitivity and JNK activity are early defects in Pink1−/− mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1−/− mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1−/− mice to inflammation and injury-induced cell death.
Highlights
Mutations in the PARK6 gene encoding PTEN-induced kinase 1 (PINK1) are the second most frequent cause for EOPD [1,2]
We further show that ablation of Pink1 results in reduced cytokine-induced nuclear factor kappa-b (NF-kB) activity in Pink12/2 embryonic fibroblasts and increased levels of interleukin 1b (IL-1b), IL-10 and IL-12 in the striatum of Pink12/2 mice challenged with a low dose of LPS
Deficient mice Homologous recombination in mouse ES cells transfected with the targeting vector led to the replacement of Pink1 exons 4 and 5 with a phosphoglycerate kinase (PGK) promoter-driven neomycin phosphotransferase expression cassette and the deletion of essential portions of the PINK1 kinase domain (Figure 1)
Summary
Mutations in the PARK6 gene encoding PINK1 are the second most frequent cause for EOPD [1,2]. Pink1-defcient mice may compensate through changes in the expression of genes that protect against the effects of Pink ablation in vivo, possibly downstream of mitochondrial dysfunction It has not been studied whether Pink deficiency affects the activity of cell death pathways implicated in PD, such as the MAP kinase pathway [22]. Transcriptional profiling data suggest that Pink deletion may cause neuroinflammation and axonal damage, which are compensated for by specific changes in gene expression While these changes may in part prevent neurodegeneration in Pink12/2 mice, increased expression of cytokines in the striatum in response to peripheral inflammation may cause enhanced sensitivity to neuroinflammation, oxidative stress and brain injury. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson’s disease (PD) display altered activity in the nigrostriatal system of Pink12/2 mice
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