Study Rationale: Both voltage-gated potassium channels and inflammatory signaling are known to be involved in Parkinson’s disease (PD). Each of these signaling systems contributes to the brain inflammation and breakdown of dopamine-producing neurons that lead to PD and its motor symptoms. Our group has proposed a hypothesis for a single coherent mechanism that links these two different facets of PD to one another, and our study aims to further explore this signaling axis as an experimental and therapeutic target. Our results could lead to new understanding of the molecular mechanisms responsible for PD pathology.
Hypothesis: We hypothesize that activation of the NLRP3 inflammasome in brain immune cells involves an outflow of potassium through the the voltage-gated potassium channel, Kv1.3. We further hypothesize that an imbalance in this system will lead over time to PD pathology.
Study Design: Using human neurons grown in the laboratory and preclinical models, we will explore the mechanistic role and cellular locations of Kv1.3 activity in PD, and we will validate this channel as a target for disease therapy. We will also determine how Kv1.3 functions in the context of NLRP3 inflammasome signaling to validate this “KI signaling axis” as a therapeutic target. We will examine the effects that specific gene deletions and pharmacological manipulation of the Kv1.3 and inflammasome signaling systems have on measures of PD progression to obtain a fuller picture of how these mechanisms work together to lead to PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: In further exploring and validating the KI signaling axis in PD, we could potentially consolidate different lines of research on Kv1.3 and NLRP3 inflammasome signaling mechanisms into a single multi-pronged therapeutic approach to PD pathology with implications for early diagnosis and prevention.
Next Steps for Development: If we successfully validate the Kv1.3 channel and the KI axis as targets for PD therapy, we will follow up by performing lead optimization studies to develop the safest, most efficient preclinical drug candidates and their combination able to act on these targets.