Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Gordon, Richard, Singh, Neeraj, Lawana, Vivek, Ghosh, Anamitra, Harischandra, Dilshan S., Jin, Huajun, Hogan, Colleen, Sarkar, Souvarish, Rokad, Dharmin, Panicker, Nikhil, Anantharam, Vellareddy, Kanthasamy, Anumantha G. and Kanthasamy, Arthi (2016) Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease. Neurobiology of Disease, 93 96-114. doi:10.1016/j.nbd.2016.04.008

Author Gordon, Richard
Singh, Neeraj
Lawana, Vivek
Ghosh, Anamitra
Harischandra, Dilshan S.
Jin, Huajun
Hogan, Colleen
Sarkar, Souvarish
Rokad, Dharmin
Panicker, Nikhil
Anantharam, Vellareddy
Kanthasamy, Anumantha G.
Kanthasamy, Arthi
Title Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease
Journal name Neurobiology of Disease   Check publisher's open access policy
ISSN 0969-9961
Publication date 2016-09-01
Sub-type Article (original research)
DOI 10.1016/j.nbd.2016.04.008
Open Access Status Not Open Access
Volume 93
Start page 96
End page 114
Total pages 19
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Language eng
Subject 2808 Neurology
Abstract Chronic microglial activation has been linked to the progressive degeneration of the nigrostriatal dopaminergic neurons evidenced in Parkinson's disease (PD) pathogenesis. The exact etiology of PD remains poorly understood. Although both oxidative stress and neuroinflammation are identified as co-contributors in PD pathogenesis, signaling mechanisms underlying neurodegenerative processes have yet to be defined. Indeed, we recently identified that protein kinase C delta (PKCδ) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors. However, it remains to be defined whether PKCδ activation contributes to immune signaling events driving microglial neurotoxicity. In the present study, we systematically investigated whether PKCδ contributes to the heightened microglial activation response following exposure to major proinflammatory stressors, including α-synuclein, tumor necrosis factor α (TNFα), and lipopolysaccharide (LPS). We report that exposure to the aforementioned inflammatory stressors dramatically upregulated PKCδ with a concomitant increase in its kinase activity and nuclear translocation in both BV-2 microglial cells and primary microglia. Importantly, we also observed a marked upregulation of PKCδ in the microglia of the ventral midbrain region of PD patients when compared to age-matched controls, suggesting a role for microglial PKCδ in neurodegenerative processes. Further, shRNA-mediated knockdown and genetic ablation of PKCδ in primary microglia blunted the microglial proinflammatory response elicited by the inflammogens, including ROS generation, nitric oxide production, and proinflammatory cytokine and chemokine release. Importantly, we found that PKCδ activated NFκB, a key mediator of inflammatory signaling events, after challenge with inflammatory stressors, and that transactivation of NFκB led to translocation of the p65 subunit to the nucleus, IκBα degradation and phosphorylation of p65 at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKCδ attenuated NFκB activation, suggesting that PKCδ regulates NFκB activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKCδ in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKCδ deficiency attenuated the proinflammatory response in the mouse substantia nigra, reduced locomotor deficits and recovered mice from sickness behavior in an LPS-induced neuroinflammation model of PD. Likewise, we found that PKCδ knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKCδ knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKCδ in PD pathology, whereby sustained PKCδ activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We conclude that inhibiting PKCδ activation may represent a novel therapeutic strategy in PD treatment.
Keyword Microglial activation
PKC delta
Dopaminergic degeneration
Parkinson's disease
Oxidative stress
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID ES10586
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 21 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 24 May 2016, 21:04:14 EST by Richard Gordon on behalf of School of Biomedical Sciences