title: PINK1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced AKT and increased p38 MAPK activation, and downregulation of EGFR.
abstract: 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.
authors: Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea.
authors: Insup
authors: I
authors: Choi
authors: Jun
authors: J
authors: Kim
authors: Hey-Kyeong
authors: HK
authors: Jeong
authors: Beomsue
authors: B
authors: Kim
authors: Ilo
authors: I
authors: Jou
authors: Sang Myun
authors: SM
authors: Park
authors: Linan
authors: L
authors: Chen
authors: Un-Jung
authors: UJ
authors: Kang
authors: Xiaoxi
authors: X
authors: Zhuang
authors: Eun-Hye
authors: EH
authors: Joe
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000172:deficiency*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D066246:ErbB Receptors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C541485:EGFR protein, mouse