| First Author | Gordon R | Year | 2016 |
| Journal | Neurobiol Dis | Volume | 93 |
| Pages | 96-114 | PubMed ID | 27151770 |
| Mgi Jnum | J:240848 | Mgi Id | MGI:5896503 |
| Doi | 10.1016/j.nbd.2016.04.008 | Citation | Gordon R, et al. (2016) Protein kinase Cdelta upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease. Neurobiol Dis 93:96-114 |
| abstractText | 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 (PKCdelta) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors. However, it remains to be defined whether PKCdelta activation contributes to immune signaling events driving microglial neurotoxicity. In the present study, we systematically investigated whether PKCdelta contributes to the heightened microglial activation response following exposure to major proinflammatory stressors, including alpha-synuclein, tumor necrosis factor alpha (TNFalpha), and lipopolysaccharide (LPS). We report that exposure to the aforementioned inflammatory stressors dramatically upregulated PKCdelta 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 PKCdelta in the microglia of the ventral midbrain region of PD patients when compared to age-matched controls, suggesting a role for microglial PKCdelta in neurodegenerative processes. Further, shRNA-mediated knockdown and genetic ablation of PKCdelta 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 PKCdelta activated NFkappaB, a key mediator of inflammatory signaling events, after challenge with inflammatory stressors, and that transactivation of NFkappaB led to translocation of the p65 subunit to the nucleus, IkappaBalpha degradation and phosphorylation of p65 at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKCdelta attenuated NFkappaB activation, suggesting that PKCdelta regulates NFkappaB activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKCdelta in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKCdelta 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 PKCdelta knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKCdelta knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKCdelta in PD pathology, whereby sustained PKCdelta activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We conclude that inhibiting PKCdelta activation may represent a novel therapeutic strategy in PD treatment. |
