Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
PLoS One. 2011 Jan 13;6(1):e16038. doi: 10.1371/journal.pone.0016038.
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 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.
Purified 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.
Increased 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.
PTEN 诱导激酶 1（PINK1）与隐性帕金森病（EOPD）有关。Pink1 缺失导致小鼠纹状体中多巴胺（DA）释放受损和线粒体呼吸减少。为了揭示与 Pink1 相关的多巴胺能功能障碍的其他机制，我们研究了纯化的脑线粒体的 Ca²+易感性、DA 水平和代谢，以及涉及帕金森病（PD）的信号通路在 Pink1⁻/⁻小鼠的黑质纹状体系统中是否显示出改变的活性。
Pink1⁻/⁻小鼠的纯化脑线粒体显示 Ca²+储存能力受损，导致 Ca²+诱导的线粒体通透性转换（mPT）增加，环孢菌素 A 可挽救这种增加。Pink1⁻/⁻小鼠黑质中的神经元亚群积累磷酸化 c-Jun，表明 JNK 活性增加。6 个月及以上的 Pink1⁻/⁻小鼠显示 DA 水平降低，与 DA 周转率增加有关。此外，Pink1⁻/⁻小鼠在脂多糖（LPS）外周挑战后纹状体中 IL-1β、IL-12 和 IL-10 水平升高，Pink1⁻/⁻胚胎成纤维细胞显示基础和炎症细胞因子诱导的核因子 kappa-β（NF-κB）活性降低。纹状体的定量转录谱分析显示，Pink1⁻/⁻小鼠差异表达基因，这些基因（i）在实验诱导的多巴胺能损伤动物中上调，（ii）调节先天免疫反应和/或细胞凋亡，以及（iii）促进轴突再生和发芽。
Pink1⁻/⁻小鼠的线粒体 Ca²+敏感性增加和 JNK 活性增加是早期缺陷，早于 DA 水平降低和异常 DA 动态平衡，并可能导致家族性 PD 中的神经元功能障碍。Pink1⁻/⁻小鼠黑质纹状体系统中的差异基因表达支持早期多巴胺能功能障碍，并表明 Pink1 缺失导致调节先天免疫反应的基因异常表达。虽然一些差异表达的基因可能减轻神经退行性变，但 LPS 诱导的脑细胞因子表达增加和细胞因子诱导的 NF-κB 激活受损可能使 Pink1⁻/⁻小鼠的神经元易患炎症和损伤诱导的细胞死亡。
