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Background  PTEN-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 Ca 2+  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 Findings  Purified brain mitochondria of  Pink1 −/−   mice showed impaired Ca 2+  storage capacity, resulting in increased Ca 2+  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.    Conclusions  Increased mitochondrial Ca 2+  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.

Increased Mitochondrial Calcium Sensitivity and Abnormal Expression of Innate Immunity Genes Precede Dopaminergic Defects in Pink1-Deficient Mice