KCa3.1 Contributes to Neuroinflammation and Nigral Dopaminergic Neurodegeneration in Experimental models of Parkinson's Disease

Samidurai, M.; Chennakesavan, K.; Sarkar, S.; Malovic, E.; Nguyen, H. M.; Singh, L.; Kumar, A.; Ealy, A.; Janarthanam, C.; Palanisamy, B. N.; Kondru, N.; Zenitsky, G.; Jin, H.; Anantharam, V.; Kanthasamy, A.; Zhang, H.; Wulff, H.

doi:10.1101/2025.03.18.643982

bioRxiv · 10.1101/2025.03.18.643982

KCa3.1 Contributes to Neuroinflammation and Nigral Dopaminergic Neurodegeneration in Experimental models of Parkinson's Disease

Samidurai, M.·Chennakesavan, K.·Sarkar, S.·Malovic, E.·Nguyen, H. M.·Singh, L.·Kumar, A.·Ealy, A.·Janarthanam, C.·Palanisamy, B. N.·Kondru, N.·Zenitsky, G.·Jin, H.·Anantharam, V.·Kanthasamy, A.·Zhang, H.·Wulff, H.

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Abstract

Chronic neuroinflammation and misfolded -synuclein (Syn) have been identified as key pathological correlates driving Parkinsons disease (PD) pathogenesis; however, the contribution of ion channels to microglia activation in the context of -synucleinopathy remains elusive. Herein, we show that KCa3.1, a calcium-activated potassium channel, is robustly upregulated within microglia in multiple preclinical models of PD and, most importantly, in human PD and dementia with Lewy bodies (DLB) brains. Pharmacological inhibition of KCa3.1 via senicapoc or TRAM-34 inhibits KCa3.1 channel activity and the associated reactive microglial phenotype in response to aggregated Syn, as well as ameliorates of PD like pathology in diverse PD mouse models. Additionally, proteomic and transcriptomic profiling of microglia revealed that senicapoc ameliorates aggregated Syn-induced, inflammation-associated pathways and dysregulated metabolism in primary microglial cells. Mechanistically, FYN kinase in a STAT1 dependent manner regulates KCa3.1 mediated the microglial reactive activation phenotype after -synucleinopathy. Moreover, reduced neuroinflammation and subsequent PD-like neuropathology were observed in SYN AAV inoculated KCa3.1 knockout mice. Together, these findings suggest that KCa3.1 inhibition represents a novel therapeutic strategy for treating patients with PD and related -synucleinopathies.

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Samidurai, M., Chennakesavan, K., Sarkar, S., Malovic, E., Nguyen, H. M., Singh, L., Kumar, A., Ealy, A., Janarthanam, C., Palanisamy, B. N., Kondru, N., Zenitsky, G., Jin, H., Anantharam, V., Kanthasamy, A., Zhang, H., Wulff, H.. 2025-03-18. KCa3.1 Contributes to Neuroinflammation and Nigral Dopaminergic Neurodegeneration in Experimental models of Parkinson's Disease. https://doi.org/10.1101/2025.03.18.643982

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