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PINK1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced AKT and increased p38 MAPK activation, and downregulation of EGFR.

Authors
Choi, I; Kim, J; Jeong, HK; Kim, B; Jou, I; Park, SM; Chen, L; Kang, UJ; Zhuang, X; Joe, EH
Citation
Glia, 61(5):800-812, 2013
Journal Title
Glia
ISSN
0894-14911098-1136
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.
MeSH terms
AnimalsAstrocytes/*metabolism/pathologyCattleCell ProliferationCells, CulturedDown-Regulation/geneticsMiceMice, 129 StrainMice, Inbred C57BLMice, KnockoutMitochondria/genetics/*metabolismProtein Kinases/*deficiencyProto-Oncogene Proteins c-akt/*antagonists & inhibitors/*metabolismReceptor, Epidermal Growth Factor/*antagonists & inhibitors/*metabolismUp-Regulation/geneticsp38 Mitogen-Activated Protein Kinases/*biosynthesis
DOI
10.1002/glia.22475
PMID
23440919
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
주, 일로박, 상면조, 은혜
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