The Fyn‐dependent voltage‐gated potassium channel Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson's disease models

Abstract

A chronic neuroinflammatory event mediated by persistent microglia activation has been well recognized as a major pathophysiological contributor to the progression of neurodegenerative processes in Parkinson's disease (PD). Identification of key targets contributing to sustained microglia activation and the regulation of these targets could provide potential treatments to halt disease progression. In this study, we show that microglial Kv1.3, a voltage‐gated potassium channel, was highly upregulated in aggregated α‐synuclein (αSyn)‐stimulated primary microglia cultures, animal models of PD, as well as in human PD postmortem samples. Importantly, patch‐clamp electrophysiological studies confirm that the observed Kv1.3 upregulation translates to increased Kv1.3 channel activity. We further demonstrate that Fyn, a non‐receptor tyrosine kinase, modulated the transcriptional upregulation of microglial Kv1.3. Using multiple state‐of‐the‐art techniques, including DuoLink PLA technology, we show that Fyn directly binds to Kv1.3 and post‐translationally modified its channel activity. Furthermore, we demonstrate the functional relevance of Kv1.3 with respect to neuroinflammation by using Kv1.3 knockout (KO) microglia and the Kv1.3‐specific pharmacological inhibitor PAP‐1. Kv1.3 KO microglial cells treated with aggregated αSyn produced fewer pro‐inflammatory cytokines. PAP‐1 significantly attenuated aggregated αSyn‐induced inflammation in both a microglial cell line and primary microglia, thus highlighting Kv1.3's importance in inflammation. Oral administration of PAP‐1 significantly inhibited MPTP‐induced neurodegeneration and inflammation in vivo. PAP‐1 also significantly reversed behavioral deficits and dopamine loss in MitoPark mice, a progressive model of PD. Our results collectively show that the Fyn‐dependent Kv1.3 channel plays an important role in inflammation in PD and has potential therapeutic implications.Support or Funding InformationES026892, NS088206, NS100090, Llyod ChairThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.