Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia
| العنوان: | Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia |
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| المؤلفون: | Huajun Jin, Hariharan Saminathan, Shivani Ghaisas, Manikandan Samidurai, Nikhil Panicker, Valina L. Dawson, Dharmin Rokad, Tae In Kam, Anumantha G. Kanthasamy, Monica R. Langley, Adhithiya Charli, Dilshan S. Harischandra, Arthi Kanthasamy, Olga Pletnikova, Matthew Neal, Souvarish Sarkar, Ted M. Dawson, Vellareddy Anantharam |
| المصدر: | The Journal of Experimental Medicine |
| بيانات النشر: | Rockefeller University Press, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | CD36 Antigens, 0301 basic medicine, Protein Folding, Inflammasomes, CD36, Interleukin-1beta, Priming (immunology), Proto-Oncogene Proteins c-fyn, 0302 clinical medicine, Immunology and Allergy, Gliosis, Research Articles, integumentary system, Microglia, biology, Chemistry, NF-kappa B, Parkinson Disease, Inflammasome, Dependovirus, Mitochondria, 3. Good health, Cell biology, Protein Kinase C-delta, medicine.anatomical_structure, alpha-Synuclein, medicine.drug, Immunology, Models, Biological, Article, Protein Aggregates, 03 medical and health sciences, Enzyme activator, FYN, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Humans, Scavenger receptor, Neuroinflammation, nervous system diseases, Enzyme Activation, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, nervous system, biology.protein, Reactive Oxygen Species, 030217 neurology & neurosurgery |
| الوصف: | Fyn kinase mediates aggregated α-synuclein (αSyn) uptake as well as αSyn-mediated proinflammatory signaling in microglia, leading to NLRP3 inflammasome activation and neuroinflammation in Parkinson’s disease. 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. |
| تدمد: | 1540-9538 0022-1007 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8bf9a3ae4bb1a5fe9de8fe5dd35e8d28Test https://doi.org/10.1084/jem.20182191Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8bf9a3ae4bb1a5fe9de8fe5dd35e8d28 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15409538 00221007 |
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