FcγRIIB mediates the inhibitory effect of aggregated α-synuclein on microglial phagocytosis

Abstract 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...

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Published in:Neurobiology of disease 2015-11, Vol.83, p.90-99
Main Authors: Choi, Yu Ree, Kang, Seo-Jun, Kim, Jin-Mo, Lee, Seung-Jae, Jou, Ilo, Joe, Eun-Hye, Park, Sang Myun
Format: Article
Language:English
Subjects:
alpha-Synuclein - metabolism
Animals
Brain - metabolism
Cells, Cultured
FcγRIIB
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microglia
Microglia - metabolism
Microglia - physiology
Neuroinflammation
Neurology
Parkinson's disease
Phagocytosis
Protein Aggregates - physiology
Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism
Rats
Rats, Sprague-Dawley
Receptors, IgG - metabolism
SHP-1
α-synuclein
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Summary:Abstract 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.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2015.08.025