Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia

Nikhil Panicker, Souvarish Sarkar, Dilshan S. Harischandra, Matthew Neal, Tae In Kam, Huajun Jin, Hariharan Saminathan, Monica Langley, Adhithiya Charli, Manikandan Samidurai, Dharmin Rokad, Shivani Ghaisas, Olga Pletnikova, Valina L. Dawson, Ted M. Dawson, Vellareddy Anantharam, Anumantha G. Kanthasamy, Arthi Kanthasamy

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1411-1430
Number of pages20
JournalJournal of Experimental Medicine
Volume216
Issue number6
DOIs
StatePublished - Jun 1 2019

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Panicker, N., Sarkar, S., Harischandra, D. S., Neal, M., Kam, T. I., Jin, H., Saminathan, H., Langley, M., Charli, A., Samidurai, M., Rokad, D., Ghaisas, S., Pletnikova, O., Dawson, V. L., Dawson, T. M., Anantharam, V., Kanthasamy, A. G., & Kanthasamy, A. (2019). Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia. Journal of Experimental Medicine, 216(6), 1411-1430. https://doi.org/10.1084/jem.20182191