Microglial Kv1.3, a voltage‐gated potassium channel, mediates neuroinflammation and neurodegeneration in cell culture and animal models of Parkinson's disease
Authors: Sarkar Souvarish , Langley Monica , Harischandra Dilshan , Neal Matthew , Luo Jie , Charli Adhithiya , Ngyen Hai Min , Jin Huajun , Ananthram Vellareddy , Kanthasamy Arthi , Wulff Heike , Kanthasamy Anumantha 
Published: November 2023

Introduction

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). Microglia constitute an attractive therapeutic target for PD because elevated microglia activation is evident during the early stages of PD pathogenesis preceding dopaminergic degeneration. Identification of key targets contributing to sustained microglia activation could provide potential targets to halt disease progression. Recently, Kv1.3, a voltage‐gated potassium channel, has gained attention due to it's potential role in inflammation in various disease including neurodegenerative diseases. Thus, we hypothesized that the Kv1.3 potassium channel may play a role in the neuroinflammatory processes in PD.

Methods

We used primary mouse microglia, the α‐syn‐AAV mouse model, the toxin‐based MPTP model, the transgenic MitoPark mouse model, post‐mortem PD brains and PD lymphocytes to determine the importance of the voltage‐gated potassium channel Kv1.3 in inflammation in PD. A pharmacological inhibitor of Kv1.3, PAP1, was used in both in‐vitro and in‐vivo PD models to determine the functional relevance of Kv1.3. Confocal microscopy, whole‐cell patch‐clamp, LCMS, Western blot, qPCR, stereology and IHC methodologies were adopted for the study.

Results

Our results from qPCR and Western blot revealed that 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. We demonstrated the functional relevance of Kv1.3 with respect to neuroinflammation by using Kv1.3 knockout microglia and a pharmacological inhibitor of this channel, PAP‐1. Kv1.3 KO microglial cells treated with aggregated αSyn had lower production of pro‐inflammatory cytokines. Further, PAP‐1 also significantly attenuated synuclein‐induced inflammation in both microglial cells and primary microglia showing the importance of this channel in inflammation. Also, PAP‐1 was able to block MPTP‐induced neurodegeneration and inflammation in‐vivo. PAP‐1 improved MPTP‐induced dopamine loss and TH neuron loss in the striatum and substantia nigra respectively. Also, PAP1 reduced microglial activation induced by MPTP.

Conclusion

Our results collectively show that Kv1.3 is highly induced in cell culture and animal models of PD and in postmortem PD brains. Blocking of Kv1.3 using a pharmacological inhibitor PAP1 reduces agg‐α‐synuclein induced inflammation in cell culture. Preclinical efficacy study in MPTP mouse model of PD showed anti‐inflammatory and neuroprotective effect. These data collectively show that Kv1.3 plays an important role in inflammation in PD and have potential therapeutic implications.

Support or Funding Information

NIH NS088206, ES026892, and Lloyd Chair