Souvarish Sarkar, Heike Wulff, Anumantha G. Kanthasamy, et al.
The role of the microglial neuroinflammatory response in the neurodegenerative process of PD was first identified over 3 decades ago, but the exact molecular mechanism underlying the sustained inflammation remains unresolved. Meta-analyses have revealed that NSAIDs can protect against neurodegenerative disorders, suggesting that an effective translational strategy to dampen neuroinflammation could offer neuroprotection in PD. Recent studies have shown that αSynAgg, a major component of Lewy bodies and neurites, can be transferred from cell to cell in a prion-like manner, leading to the spread of disease pathology. Although αSynAgg can induce inflammation in cell cultures and animal models of PD, the downstream signaling mechanism is not well understood.
In this study, researchers show that the microglial Kv1.3 potassium channel was highly upregulated in response to αSynAgg. Further, they show that surface Kv1.3 expression levels increased to a much greater degree than whole-cell protein levels, suggesting that the trafficking of Kv1.3 to the surface plays an important role in this upregulation.
Previous studies have reported that adaptor protein 1 (AP-1), which is responsible for clathrin-coated vesicle formation, governs Kv1.3 trafficking and that Fyn plays an important role in governing AP-1 expression. Therefore, future studies looking into the role of the Fyn/
AP-1 axis in αSynAgg-induced Kv1.3 trafficking are warranted.
Sarkar et al. observed the induction of Kv1.3 in multiple in vivo models of PD, recapitulating various key hallmarks of PD. Moreover, they found that Kv1.3 was also upregulated in patients with Parkinsonian syndrome and dementia with Lewy bodies, demonstrating the clinical relevance of their findings. This upregulation was proximally controlled by the Fyn/PKCδ kinase signaling cascade.
These findings further demonstrate a probable Kv1.3-mediated signaling cascade that can modulate microglial inflammation in Parkinsonism. Comprehensive preclinical evaluation of the Kv1.3 blocker PAP-1 in 3 different animal models of PD, including MitoPark transgenic, MPTP, and αSynPFF mouse models, provides credence to the translational relevance of Kv1.3 modulation in PD. The diverse roles of Kv1.3 emerging from these findings, together with other studies, reinforce the potential therapeutic implications of Kv1.3 modulators.
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