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- Title
Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson's disease.
- Authors
Sarkar, Souvarish; Nguyen, Hai M.; Malovic, Emir; Jie Luo; Langley, Monica; Palanisamy, Bharathi N.; Singh, Neeraj; Manne, Sireesha; Neal, Matthew; Gabrielle, Michelle; Abdalla, Ahmed; Anantharam, Poojya; Rokad, Dharmin; Panicker, Nikhil; Singh, Vikrant; Ay, Muhammet; Charli, Adhithiya; Harischandra, Dilshan; Lee-Way Jin; Huajun Jin
- Abstract
Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson's disease (PD), and optimal modulation of these targets can provide potential treatments to halt disease progression. Here, we demonstrated that microglial Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated in response to aggregated α-synuclein (αSynAgg) stimulation in primary microglial cultures and animal models of PD, as well as in postmortem human PD brains. Patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translated to increased Kv1.3 channel activity. The kinase Fyn, a risk factor for PD, modulated transcriptional upregulation and posttranslational modification of microglial Kv1.3. Multiple state-of-the-art analyses, including Duolink proximity ligation assay imaging, revealed that Fyn directly bound to Kv1.3 and posttranslationally modified its channel activity. Furthermore, we demonstrated the functional relevance of Kv1.3 in augmenting the neuroinflammatory response by using Kv1.3-KO primary microglia and the Kv1.3-specific small-molecule inhibitor PAP-1, thus highlighting the importance of Kv1.3 in neuroinflammation. Administration of PAP-1 significantly inhibited neurodegeneration and neuroinflammation in multiple animal models of PD. Collectively, our results imply that Fyn-dependent regulation of Kv1.3 channels plays an obligatory role in accentuating the neuroinflammatory response in PD and identify Kv1.3 as a potential therapeutic target for PD.
- Subjects
PARKINSON'S disease; INFLAMMATION; THERAPEUTICS; POTASSIUM antagonists; POST-translational modification; POTASSIUM channels; CELL metabolism; DRUG therapy for Parkinson's disease; PROTEINS; RESEARCH; NERVE tissue proteins; ANIMAL experimentation; RESEARCH methodology; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; CELLS; RESEARCH funding; MEMBRANE proteins; MICE; CHEMICAL inhibitors
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 8, p4195
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI136174