A sustained neuroinflammatory insult characterized by massive microglia activation has been well recognized as a major pathophysiological contributor to the progression of neurodegenerative processes in Parkinson?s disease (PD). Interestingly, microglia constitute a particularly attractive therapeutic target for PD because elevated microglia activation is evident during the early stages of PD pathogenesis preceding dopaminergic degeneration. Recent studies pertaining to neuroinflammation in PD have generated tremendous enthusiasm because ?-synuclein (?Sn) aggregates can serve as an endogenous antigen triggering neurotoxicity by provoking a potent microglia-mediated proinflammatory response. Also, accumulating evidence reveals that misfolded ?Syn spreads through a cell-to-cell transmission mechanism, contributing to the propagation of ? yn pathology to neighboring neuronal and glial cells, possibly augmenting the progression of PD. Despite these advances, the fundamental neurobiological mechanisms regulating sustained microglia activation and neuroinflammatory cascades during pathogenic ?Syn aggregate stimulation remain to be established. Thus, identification of key targets contributing to sustained microglia activation could provide potential targets to slow the progression of the disease. We recently obtained exciting new data showing that the voltage-gated potassium channel Kv1.3 is highly upregulated in aggregated ?Syn-stimulated primary microglia and animal models of PD, as well as in human PD postmortem samples. Importantly, patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translates to increased Kv1.3 channel activity. Additional preliminary results suggest that a proinflammatory kinase PKC? plays a role in ?Syn aggregate-induced Kv1.3 upregulation. To further expand our novel preliminary results, we will systematically pursue the following specific aims: (i) characterize Kv1.3 upregulation and activation of pro-inflammatory microglia in animal models of ?Syn aggregate-induced neurotoxicity, and define the role of Kv1.3 in microglia-mediated neuroinflammation and augmentation of the neurodegenerative process in nigrostriatal dopaminergic neurons in PD, (ii) unravel the molecular underpinning of Kv1.3 channel upregulation in microglia during an ?Syn aggregate-induced neuroinflammatory insult, and (iii) establish the role of Kv1.3 in mediating the proinflammatory response in the nigrostriatal dopaminergic system during ?Syn protein aggregation in animal models of PD. We will use multiple model systems and state-of-the-art biochemical, cellular, neurophysiological, histological and neurochemical approaches to achieve these specific aims. Overall, we anticipate that our proposed studies will provide novel mechanistic insights into sustained microglia activation and its role in neuroinflammatory processes in PD disease progression and will offer novel therapeutic targets to curtail neuroinflammatory responses in PD and other related neurodegenerative disorders.
Chronic neuroinflammation characterized by persistent microglia activation resulting in substantial release of proinflammatory cytokines and chemokines is a key pathologic feature of Parkinson?s disease (PD). Given that abnormal ?Synuclein protein aggregates can trigger the chronic brain inflammatory process, we propose to characterize the role of the major voltage-gated potassium channel Kv1.3 during ?Syn aggregate-induced inflammatory responses in cell culture and animal models of PD as well as in human PD brain samples. Our study will provide new insights into the neuroinflammatory pathogenesis of PD and may offer new treatment strategies to slow down the progression of Parkinson?s disease.
| Sarkar, Souvarish; Malovic, Emir; Sarda, Deeksha et al. (2018) Characterization and comparative analysis of a new mouse microglial cell model for studying neuroinflammatory mechanisms during neurotoxic insults. Neurotoxicology 67:129-140 |
| Gordon, Richard; Albornoz, Eduardo A; Christie, Daniel C et al. (2018) Inflammasome inhibition prevents ?-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med 10: |
