Modulation of microglial Kv1.3-dependent neuroinflammation as a potential therapeutic strategy for Parkinson's disease

The pathology of Parkinson’s disease (PD) arises from α-Synuclein (α-Syn) aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) with impairment of the nigrostriatal dopaminergic pathway. Previous results have shown α-Syn to mediate the upregulation of the microglial voltage-gated potassium (K+) channel Kv1.3, which is mechanistically coupled with NLRP3 inflammasome activation in microglia in a potassium efflux-dependent manner, thus sustaining the three major facets of PD. Therefore, a reduction in microglial NLRP3 inflammasome activation mediated by microglial Kv1.3 inhibition is expected to rescue an anti-inflammatory phenotype in the brain, thus limiting dopaminergic neurodegeneration. Accordingly, we found that deletion of Kv1.3 in microglia rescues dopaminergic neurons cell loss, reduces pro-inflammatory microglia activation, and limits astrogliosis. Overall, these results underline the relevance of microglial Kv1.3 in mediating the neuroinflammatory response in PD, thus constituting a potential therapeutic target for the treatment of this disease.