title: Fyn Kinase Regulates Microglial Neuroinflammatory Responses in Cell Culture and Animal Models of Parkinson's Disease.
abstract: Sustained neuroinflammation mediated by resident microglia is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson's disease (PD), but the key molecular signaling events regulating persistent microglial activation have yet to be clearly defined. In the present study, we examined the role of Fyn, a non-receptor tyrosine kinase, in microglial activation and neuroinflammatory mechanisms in cell culture and animal models of PD. The well-characterized inflammogens LPS and TNFα rapidly activated Fyn kinase in microglia. Immunocytochemical studies revealed that activated Fyn preferentially localized to the microglial plasma membrane periphery and the nucleus. Furthermore, activated Fyn phosphorylated PKCδ at tyrosine residue 311, contributing to an inflammogen-induced increase in its kinase activity. Notably, the Fyn-PKCδ signaling axis further activated the LPS- and TNFα-induced MAP kinase phosphorylation and activation of the NFκB pathway, implying that Fyn is a major upstream regulator of proinflammatory signaling. Functional studies in microglia isolated from wild-type (Fyn(+/+)) and Fyn knock-out (Fyn(-/-)) mice revealed that Fyn is required for proinflammatory responses, including cytokine release as well as iNOS activation. Interestingly, a prolonged inflammatory insult induced Fyn transcript and protein expression, indicating that Fyn is upregulated during chronic inflammatory conditions. Importantly, in vivo studies using MPTP, LPS, or 6-OHDA models revealed a greater attenuation of neuroinflammatory responses in Fyn(-/-) and PKCδ (-/-) mice compared with wild-type mice. Collectively, our data demonstrate that Fyn is a major upstream signaling mediator of microglial neuroinflammatory processes in PD.
  
  
  CONCLUSIONS
  Parkinson's disease (PD) is a complex multifactorial disease characterized by the progressive loss of midbrain dopamine neurons. Sustained microglia-mediated neuroinflammation has been recognized as a major pathophysiological contributor to chronic degenerative processes in PD; however, the key molecular signaling mechanisms underlying microglial activation are not entirely clear. Herein, we identified a novel role for the non-receptor tyrosine kinase Fyn in regulating neuroinflammatory responses in microglia. Our data clearly suggest that the Fyn-PKCδ signaling axis acts as a major upstream signaling mediator of the sustained neuroinflammatory processes in cell culture and animal models of PD. Our finding has important clinical significance to PD because it identifies Fyn as a potential translational target for intervention of progressive neurodegenerative processes in PD.
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Panicker
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Saminathan
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Matthew
authors.initials: M
authors.lastname: Neal
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Dilshan S
authors.identifier: http://orcid.org/0000-0003-3220-8765
authors.initials: DS
authors.lastname: Harischandra
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Richard
authors.initials: R
authors.lastname: Gordon
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Kavin
authors.initials: K
authors.lastname: Kanthasamy
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Vivek
authors.initials: V
authors.lastname: Lawana
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Souvarish
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011.
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011 arthik@iastate.edu.
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
mesh_terms: D000818:Animals; D002458:Cell Fractionation / Q000379:methods; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications* / Q000209:etiology; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014443:Tyrosine; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D014443:Tyrosine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051745:Protein Kinase C-delta
keywords: Fyn; Parkinson's disease; kinase; microglia; neuroinflammation; phosphorylation