Neuroinflammation and microglial Kv1.3 in Parkinsons disease

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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 α-synuclein (αSn) aggregates can serve as an endogenous antigen triggering neurotoxicity by provoking a potent microglia-mediated proinflammatory response. Also, accumulating evidence reveals that misfolded αSyn spreads through a cell-to-cell transmission mechanism, contributing to the propagation of α 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 αSyn 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 αSyn-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 PKCδ plays a role in αSyn 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 αSyn 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 αSyn aggregate-induced neuroinflammatory insult, and (iii) establish the role of Kv1.3 in mediating the proinflammatory response in the nigrostriatal dopaminergic system during αSyn 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.