Fyn Kinase Regulates Microglial Neuroinflammatory Responses in Cell Culture and Animal Models of Parkinson's Disease

• DOI: 10.1523/jneurosci.0302-15.2015
• Publication Date: 2015-07-08T16:31:02Z
• Authors: N. Panicker; H. Saminathan; H. Jin; M. Neal; D. S. Harischandra; R. Gordon; K. Kanthasamy; V. Lawana; S. Sarkar; J. Luo; V. Anantharam; A. G. Kanthasamy; A. Kanthasamy
• Keywords: FYN; Proinflammatory cytokine; Src family kinase

Sustained neuroinflammation mediated by resident microglia is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson9s disease (PD), but the molecular signaling events regulating persistent microglial activation have yet be clearly defined. In present study, we examined role of Fyn, non-receptor tyrosine kinase, in and neuroinflammatory mechanisms cell culture animal models PD. The well-characterized inflammogens LPS TNFα rapidly activated Fyn kinase microglia. Immunocytochemical studies revealed that preferentially localized plasma membrane periphery nucleus. Furthermore, phosphorylated PKCδ at residue 311, contributing an inflammogen-induced increase its activity. Notably, Fyn-PKCδ axis further LPS- TNFα-induced MAP phosphorylation NFκB pathway, implying major upstream regulator proinflammatory signaling. Functional isolated from wild-type (Fyn^+/+) knock-out (Fyn^−/−) mice required for responses, cytokine release well iNOS activation. Interestingly, prolonged inflammatory insult induced transcript protein expression, indicating upregulated during chronic conditions. Importantly, <i>in vivo</i> using MPTP, LPS, or 6-OHDA greater attenuation responses Fyn^−/− ^−/− compared with mice. Collectively, our data demonstrate mediator processes <b>SIGNIFICANCE STATEMENT</b> (PD) complex multifactorial characterized progressive loss midbrain dopamine neurons. microglia-mediated has been degenerative PD; however, underlying are not entirely clear. Herein, identified novel Our suggest acts sustained finding important clinical significance PD because it identifies potential translational target intervention