| First Author | Akundi RS | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 1 | Pages | e16038 |
| PubMed ID | 21249202 | Mgi Jnum | J:169471 |
| Mgi Id | MGI:4941086 | Doi | 10.1371/journal.pone.0016038 |
| Citation | Akundi RS, et al. (2011) Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS One 6(1):e16038 |
| abstractText | 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-1beta, 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-beta (NF-kappaB) 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-kappaB activation may predispose neurons of Pink1/ mice to inflammation and injury-induced cell death. |
