FcγRIIB mediates the inhibitory effect of aggregated α-synuclein on microglial phagocytosis.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Although the etiology of PD has not yet been fully understood, accumulating evidence indicates that neuroinflammation plays a critical role in the progression of PD. α-Synuclein (α-Syn) has been considered to be a key player of the pathogenesis of PD, and recent reports that prion-like propagation of misfolded α-syn released from neurons may play an important role in the progression of PD have led to increased attention to the studies elucidating the roles of extracellular α-syn in the CNS. Extracellular α-syn has also been reported to regulate microglial inflammatory response. In this study, we demonstrated that aggregated α-syn inhibited microglial phagocytosis by activating SHP-1. SHP-1 activation was also observed in A53T α-syn transgenic mice. In addition, aggregated α-syn bound to FcγRIIB on microglia, inducing SHP-1 activation, further inhibiting microglial phagocytosis. Aggregated α-syn upregulated FcγRIIB expression in microglia and upregulated FcγRIIB was also observed in A53T α-syn transgenic mice. These data suggest that aggregated α-syn released from neurons dysregulates microglial immune response through inhibiting microglial phagocytosis, further causing neurodegeneration observed in PD. The interaction of aggregated α-syn and FcγRIIB and further SHP-1 activation can be a new therapeutic target against PD.
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea; Neuroscience graduate program, Department of Biological Sciences, Ajou University School of Medicine, Suwon, Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Yu Ree
YR
Choi
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea; Neuroscience graduate program, Department of Biological Sciences, Ajou University School of Medicine, Suwon, Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Seo-Jun
SJ
Kang
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Jin-Mo
JM
Kim
Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea.
Seung-Jae
SJ
Lee
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea; Neuroscience graduate program, Department of Biological Sciences, Ajou University School of Medicine, Suwon, Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Ilo
I
Jou
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea; Neuroscience graduate program, Department of Biological Sciences, Ajou University School of Medicine, Suwon, Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Eun-Hye
EH
Joe
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea; Neuroscience graduate program, Department of Biological Sciences, Ajou University School of Medicine, Suwon, Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea. Electronic address: sangmyun@ajou.ac.kr.
Sang Myun
SM
Park
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000502:physiology*; D010587:Phagocytosis; D066329:Protein Aggregates / Q000502:physiology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017452:Receptors, IgG / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
C499172:Fcgr2b protein, mouse; D066329:Protein Aggregates; D017452:Receptors, IgG; D051844:alpha-Synuclein; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
FcγRIIB; Microglia; Neuroinflammation; Parkinson's disease; Phagocytosis; SHP-1; α-synuclein