Alpha-synuclein induces migration of BV-2 microglial cells by up-regulation of CD44 and MT1-MMP.
Although there is known to be a marked concentration of reactive microglia in the substantia nigra pars compacta (SNpc) of patients with Parkinson's disease (PD), a disorder in which alpha-synuclein plays a key pathogenic role, the specific roles of alpha-synuclein and microglia remains poorly understood. In this study, we investigated the effects of alpha-synuclein and the mechanisms of invasive microglial migration into the SNpc. We show that alpha-synuclein up-regulates the expressions of the cell adhesion molecule CD44 and the cell surface protease membrane-type 1 matrix metalloproteinase through the extracellular regulated kinases 1/2 pathway. These concurrent inductions increased the generation of soluble CD44 to liberate microglia from the surrounding extracellular matrix for migration. The effects of alpha-synuclein were identical in BV-2 murine microglial cells subjected to cDNA transfection and extracellular treatment. These inductions in primary microglial cultures of C57Bl/6 mice were identical to those in BV-2 cells. alpha-Synuclein-induced microglial migration into the SNpc was confirmed in vivo using a 6-hydroxydopamine mouse model of PD. Our data demonstrate a correlation between alpha-synuclein-induced phenotypic changes and microglial migration. With the recruitment of the microglial population into the SNpc during dopaminergic neurodegeneration, alpha-synuclein may play a role in accelerating the pathogenesis of PD.
Kim
Seonghan
S
Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, Korea.
Cho
Seo-Hyun
SH
Kim
Ka Young
KY
Shin
Ki Young
KY
Kim
Hye-Sun
HS
Park
Cheol-Hyoung
CH
Chang
Keun-A
KA
Lee
Sang Hyung
SH
Cho
Daeho
D
Suh
Yoo-Hun
YH
D000818:Animals; D001921:Brain / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism / Q000601:surgery; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics / Q000502:physiology*
D017077:Culture Media, Conditioned; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D016627:Oxidopamine; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D053511:Matrix Metalloproteinase 14