Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of parkinson’s disease

Panicker, Nikhil, Saminathan, Hariharan, Jin, Huajun, Neal, Matthew, Harischandra, Dilshan S., Gordon, Richard, Kanthasamy, Kavin, Lawana, Vivek, Sarkar, Souvarish, Luo, Jie, Anantharam, Vellareddy, Kanthasamy, Anumantha G. and Kanthasamy, Arthi (2015) Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of parkinson’s disease. Journal of Neuroscience, 35 27: 10058-10077. doi:10.1523/JNEUROSCI.0302-15.2015

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Author Panicker, Nikhil
Saminathan, Hariharan
Jin, Huajun
Neal, Matthew
Harischandra, Dilshan S.
Gordon, Richard
Kanthasamy, Kavin
Lawana, Vivek
Sarkar, Souvarish
Luo, Jie
Anantharam, Vellareddy
Kanthasamy, Anumantha G.
Kanthasamy, Arthi
Title Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of parkinson’s disease
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 1529-2401
Publication date 2015-07-08
Year available 2015
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.0302-15.2015
Open Access Status File (Publisher version)
Volume 35
Issue 27
Start page 10058
End page 10077
Total pages 20
Place of publication Washington, United States
Publisher Society for Neuroscience
Language eng
Formatted 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.
Keyword Fyn
Parkinson’s disease
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 29 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 14 Oct 2015, 03:21:15 EST by Richard Gordon on behalf of Scholarly Communication and Digitisation Service