PINK1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced AKT and increased p38 MAPK activation, and downregulation of EGFR.
PINK1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced AKT and increased p38 MAPK activation, and downregulation of EGFR.
复制标题
作者：
Choi, Insup;Kim, Jun;Jeong, Hey-Kyeong;Kim, Beomsue;Jou, Ilo;Park, Sang Myun;Chen, Linan;Kang, Un-Jung;Zhuang, Xiaoxi;Joe, Eun-hye
PINK 1（PTEN诱导的推定激酶1）是一种家族性帕金森病（PD）相关基因，在星形胶质细胞中表达，但对其在这种细胞类型中的作用知之甚少。在这里，我们发现，从PINK 1基因敲除（KO）小鼠培养的星形胶质细胞表现出缺陷的增殖反应，表皮生长因子（EGF）和胎牛血清。在PINK 1-KO星形胶质细胞中，基础和EGF诱导的p38活化（磷酸化）增加，而EGF受体（EGFR）表达和AKT活化降低。p38抑制（SB 203580）或用小干扰RNA（siRNA）敲低挽救了PINK 1-KO星形胶质细胞中的EGFR表达和AKT活化。PINK 1-KO星形胶质细胞的增殖缺陷似乎与线粒体缺陷有关，表现为线粒体质量和膜电位降低、细胞内活性氧水平升高、葡萄糖摄取能力降低和ATP产生减少。线粒体毒素（寡霉素）和葡萄糖摄取抑制剂（根皮素）模拟PINK 1缺陷表型，减少星形胶质细胞增殖，EGFR表达和AKT激活，并增加p38激活。此外，PINK 1-KO星形胶质细胞的增殖缺陷导致伤口愈合过程延迟。总之，这些结果表明，PINK 1缺陷导致星形胶质细胞功能障碍，这可能有助于PD的发展，由于星形胶质细胞介导的大脑微环境修复延迟。
PINK1 (PTEN induced putative kinase 1), a familial Parkinson's disease (PD)-related gene, is expressed in astrocytes, but little is known about its role in this cell type. Here, we found that astrocytes cultured from PINK1-knockout (KO) mice exhibit defective proliferative responses to epidermal growth factor (EGF) and fetal bovine serum. In PINK1-KO astrocytes, basal and EGF-induced p38 activation (phosphorylation) were increased whereas EGF receptor (EGFR) expression and AKT activation were decreased. p38 inhibition (SB203580) or knockdown with small interfering RNA (siRNA) rescued EGFR expression and AKT activation in PINK1-KO astrocytes. Proliferation defects in PINK1-KO astrocytes appeared to be linked to mitochondrial defects, manifesting as decreased mitochondrial mass and membrane potential, increased intracellular reactive oxygen species level, decreased glucose-uptake capacity, and decreased ATP production. Mitochondrial toxin (oligomycin) and a glucose-uptake inhibitor (phloretin) mimicked the PINK1-deficiency phenotype, decreasing astrocyte proliferation, EGFR expression and AKT activation, and increasing p38 activation. In addition, the proliferation defect in PINK1-KO astrocytes resulted in a delay in the wound healing process. Taken together, these results suggest that PINK1 deficiency causes astrocytes dysfunction, which may contribute to the development of PD due to delayed astrocytes-mediated repair of microenvironment in the brain.
登录
查看更多内容
DOI：
10.1074/jbc.m110.137034
发表时间：
2010-12-17
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Ishikawa S;Taira T;Takahashi-Niki K;Niki T;Ariga H;Iguchi-Ariga SM
通讯作者：
Iguchi-Ariga SM
影响因子：
3.7
作者：
Abramov AY;Gegg M;Grunewald A;Wood NW;Klein C;Schapira AH
通讯作者：
Schapira AH
影响因子：
3.4
作者：
Hinterkeuser, S;Schröder, W;Steinhäuser, C
通讯作者：
Steinhäuser, C
影响因子：
3.4
作者：
Fernandez-Gonzalez, A;Pérez-Otaño, I;Morgan, JI
通讯作者：
Morgan, JI
DOI：
10.1073/pnas.0705363105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Haque, M. Emdadul;Thomas, Kelly J.;Park, David S.
通讯作者：
Park, David S.