TY - JOUR
T1 - Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia
AU - Panicker, Nikhil
AU - Sarkar, Souvarish
AU - Harischandra, Dilshan S.
AU - Neal, Matthew
AU - Kam, Tae In
AU - Jin, Huajun
AU - Saminathan, Hariharan
AU - Langley, Monica
AU - Charli, Adhithiya
AU - Samidurai, Manikandan
AU - Rokad, Dharmin
AU - Ghaisas, Shivani
AU - Pletnikova, Olga
AU - Dawson, Valina L.
AU - Dawson, Ted M.
AU - Anantharam, Vellareddy
AU - Kanthasamy, Anumantha G.
AU - Kanthasamy, Arthi
N1 - Funding Information:
This study was supported by the National Institutes of Health (grants NS088206, ES026892, and NS100090). The W.E. Lloyd
Funding Information:
Endowed Chair and Eminent Scholar in Veterinary Medicine and Armbrust Endowment (to A.G. Kanthasamy) and the Salisbury Endowed Chair (to A. Kanthasamy) are also acknowledged. The Johns Hopkins University Alzheimer’s Disease Research Center Grant (National Institutes of Health grant P50 AG05146) and the Institutional Center Core Grant to the Johns Hopkins Multiphoton Imaging Core (National Institutes of Health grant NS050274) are acknowledged. N. Panicker is supported by a postdoctoral fellowship from the Maryland Stem Cell Research Fund (2017-MSCRFF-3838).
Publisher Copyright:
© 2019 Panicker et al.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson’s disease (PD), but the cell-signaling mechanisms governing chronic neuroinflammation are not well understood. Here, we show that Fyn kinase, in conjunction with the class B scavenger receptor CD36, regulates the microglial uptake of aggregated human α-synuclein (αSyn), which is the major component of PD-associated Lewy bodies. αSyn can effectively mediate LPS-independent priming and activation of the microglial NLRP3 inflammasome. Fyn kinase regulates both of these processes; it mediates PKCδ-dependent NF-κB–p65 nuclear translocation, leading to inflammasome priming, and facilitates αSyn import into microglia, contributing to the generation of mitochondrial reactive oxygen species and consequently to inflammasome activation. In vivo experiments using A53T and viral-αSyn overexpression mouse models as well as human PD neuropathological results further confirm the role of Fyn in NLRP3 inflammasome activation. Collectively, our study identifies a novel Fynmediated signaling mechanism that amplifies neuroinflammation in PD.
AB - Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson’s disease (PD), but the cell-signaling mechanisms governing chronic neuroinflammation are not well understood. Here, we show that Fyn kinase, in conjunction with the class B scavenger receptor CD36, regulates the microglial uptake of aggregated human α-synuclein (αSyn), which is the major component of PD-associated Lewy bodies. αSyn can effectively mediate LPS-independent priming and activation of the microglial NLRP3 inflammasome. Fyn kinase regulates both of these processes; it mediates PKCδ-dependent NF-κB–p65 nuclear translocation, leading to inflammasome priming, and facilitates αSyn import into microglia, contributing to the generation of mitochondrial reactive oxygen species and consequently to inflammasome activation. In vivo experiments using A53T and viral-αSyn overexpression mouse models as well as human PD neuropathological results further confirm the role of Fyn in NLRP3 inflammasome activation. Collectively, our study identifies a novel Fynmediated signaling mechanism that amplifies neuroinflammation in PD.
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U2 - 10.1084/jem.20182191
DO - 10.1084/jem.20182191
M3 - Article
C2 - 31036561
AN - SCOPUS:85067214404
SN - 0022-1007
VL - 216
SP - 1411
EP - 1430
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
ER -