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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 Fyn-mediated signaling mechanism that amplifies neuroinflammation in PD.

Titel:	Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia.
Autor/in / Beteiligte Person:	Panicker, N ; Sarkar, S ; Harischandra, DS ; Neal, M ; Kam, TI ; Jin, H ; Saminathan, H ; Langley, M ; Charli, A ; Samidurai, M ; Rokad, D ; Ghaisas, S ; Pletnikova, O ; Dawson, VL ; Dawson, TM ; Anantharam, V ; Kanthasamy, AG ; Kanthasamy, A
Link:	Full Text Finder (Volltext)
Zeitschrift:	The Journal of experimental medicine, Jg. 216 (2019-06-03), Heft 6, S. 1411-1430
Veröffentlichung:	New York, NY : Rockefeller University Press, 2019
Medientyp:	academicJournal
ISSN:	1540-9538 (electronic)
DOI:	10.1084/jem.20182191
Schlagwort:	Animals CD36 Antigens metabolism Dependovirus metabolism Disease Models, Animal Enzyme Activation Gliosis metabolism Gliosis pathology Humans Interleukin-1beta metabolism Mice, Inbred C57BL Mitochondria metabolism Models, Biological NF-kappa B metabolism Parkinson Disease metabolism Parkinson Disease pathology Protein Aggregates Protein Kinase C-delta metabolism Proto-Oncogene Proteins c-fyn deficiency Reactive Oxygen Species metabolism Inflammasomes metabolism Microglia metabolism NLR Family, Pyrin Domain-Containing 3 Protein metabolism Protein Folding Proto-Oncogene Proteins c-fyn metabolism alpha-Synuclein chemistry alpha-Synuclein metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [J Exp Med] 2019 Jun 03; Vol. 216 (6), pp. 1411-1430. <i>Date of Electronic Publication: </i>2019 Apr 29. MeSH Terms: Protein Folding* ; Inflammasomes / metabolism ; Microglia / metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein / metabolism ; Proto-Oncogene Proteins c-fyn / metabolism ; alpha-Synuclein / chemistry ; alpha-Synuclein / metabolism ; Animals ; CD36 Antigens / metabolism ; Dependovirus / metabolism ; Disease Models, Animal ; Enzyme Activation ; Gliosis / metabolism ; Gliosis / pathology ; Humans ; Interleukin-1beta / metabolism ; Mice, Inbred C57BL ; Mitochondria / metabolism ; Models, Biological ; NF-kappa B / metabolism ; Parkinson Disease / metabolism ; Parkinson Disease / pathology ; Protein Aggregates ; Protein Kinase C-delta / metabolism ; Proto-Oncogene Proteins c-fyn / deficiency ; Reactive Oxygen Species / metabolism References: J Neural Transm (Vienna). 2000;107(3):335-41. (PMID: 10821442) ; J Neurosci. 2001 Mar 15;21(6):2039-47. (PMID: 11245687) ; J Biol Chem. 2002 Dec 6;277(49):47373-9. (PMID: 12239221) ; Acta Neuropathol. 2003 Dec;106(6):518-26. 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(PMID: 9197268) ; Nat Genet. 1998 Feb;18(2):106-8. (PMID: 9462735) ; Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. (PMID: 9600986) ; Ann Neurol. 1998 Sep;44(3):415-22. (PMID: 9749615) Grant Information: P30 NS050274 United States NS NINDS NIH HHS; P50 AG005146 United States AG NIA NIH HHS; R01 NS100090 United States NS NINDS NIH HHS; U01 NS112008 United States NS NINDS NIH HHS; R01 ES026892 United States ES NIEHS NIH HHS; R01 NS088206 United States NS NINDS NIH HHS Substance Nomenclature: 0 (CD36 Antigens) ; 0 (Inflammasomes) ; 0 (Interleukin-1beta) ; 0 (NF-kappa B) ; 0 (NLR Family, Pyrin Domain-Containing 3 Protein) ; 0 (Protein Aggregates) ; 0 (Reactive Oxygen Species) ; 0 (alpha-Synuclein) ; EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn) ; EC 2.7.11.13 (Protein Kinase C-delta) Entry Date(s): Date Created: 20190501 Date Completed: 20200414 Latest Revision: 20230323 Update Code: 20240513 PubMed Central ID: PMC6547864

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