Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice.
Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice.
复制标题
DOI：
10.1371/journal.pone.0016038
复制
发表时间：
2011-01-13
期刊：
影响因子：
3.7
通讯作者：
Büeler H
中科院分区：
文献类型：
--
作者：
Akundi RS;Huang Z;Eason J;Pandya JD;Zhi L;Cass WA;Sullivan PG;Büeler H
PTEN诱导的激酶1（PINK 1）与隐性帕金森综合征（EOPD）有关。Pink 1缺失导致小鼠纹状体多巴胺（DA）释放受损和线粒体呼吸减少。为了揭示Pink 1相关多巴胺能功能障碍的其他机制，我们研究了纯化脑线粒体的Ca 2+脆弱性，DA水平和代谢，以及与帕金森病（PD）有关的信号通路是否在Pink 1 −/−小鼠的黑质纹状体系统中显示出改变的活性。Pink 1 −/−小鼠的纯化脑线粒体显示Ca 2+储存能力受损，导致Ca 2+诱导的线粒体通透性转换（mPT）增加，这是由环孢素A拯救的。Pink 1 −/−小鼠黑质中的一个神经元亚群积累了磷酸-c-Jun，表明Jun N-末端激酶（JNK）活性增加。6个月及以上的Pink 1 −/−小鼠表现出与DA周转增加相关的DA水平降低。此外，Pink 1 −/−小鼠在脂多糖（LPS）外周激发后纹状体中的IL-1β、IL-12和IL-10水平升高，Pink 1 −/−胚胎成纤维细胞显示基础和炎性丝氨酸诱导的核因子κ-β（NF-κB）活性降低。纹状体中的定量转录谱显示，Pink 1 −/−小鼠差异表达基因，（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/或凋亡，（iii）促进轴突再生和发芽。线粒体Ca 2+敏感性和JNK活性增加是Pink 1 −/−小鼠的早期缺陷，先于DA水平降低和DA稳态异常，可能导致家族性PD的神经元功能障碍。Pink 1 −/−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Pink 1缺失导致调节先天免疫反应的基因表达异常。虽然一些差异表达的基因可能会减轻神经变性，但LPS诱导的脑细胞因子表达增加和精氨酸诱导的NF-κB活化受损可能会使Pink 1 −/−小鼠的神经元易于发生炎症和损伤诱导的细胞死亡。
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.
登录
查看更多内容
影响因子：
3.3
作者：
Desteno, D. A.;Schmauss, C.
通讯作者：
Schmauss, C.
线粒体质量控制：有关帕金森氏病与pink1，Parkin和Omi/Htra2相关的见解，以保持线粒体稳态。
影响因子：
3
作者：
Dagda, Ruben K.;Chu, Charleen T.
通讯作者：
Chu, Charleen T.
DOI：
10.1073/pnas.0500346102
发表时间：
2005-07-19
影响因子：
11.1
作者：
Cha, GH;Kim, S;Cho, KS
通讯作者：
Cho, KS
影响因子：
4.8
作者：
Chen, G;Bower, KA;Luo, J
通讯作者：
Luo, J
影响因子：
6.1
作者：
Cintia Ferrari, Carina;Pott Godoy, Maria Clara;Juan Pitossi, Fernando
通讯作者：
Juan Pitossi, Fernando