201. Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson’s disease
- Author
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Jie Luo, Vellareddy Anantharam, Poojya Anantharam, Srikant Rangaraju, Anumantha G. Kanthasamy, Heike Wulff, Dilshan S. Harischandra, Neeraj Kumar Singh, Bharathi N. Palanisamy, Sireesha Manne, Vikrant Singh, Lee-Way Jin, Nikhil Panicker, Hai M. Nguyen, Matthew Neal, Huajun Jin, Muhammet Ay, Dharmin Rokad, Ahmed Abdalla, Souvarish Sarkar, Monica R. Langley, Adhithiya Charli, Emir Malovic, and Michelle Gabrielle
- Subjects
0301 basic medicine ,Parkinson's disease ,Proximity ligation assay ,Proto-Oncogene Proteins c-fyn ,complex mixtures ,Mice ,03 medical and health sciences ,0302 clinical medicine ,FYN ,Downregulation and upregulation ,medicine ,Animals ,Humans ,natural sciences ,Neuroinflammation ,Inflammation ,Mice, Knockout ,Kv1.3 Potassium Channel ,Microglia ,urogenital system ,Kinase ,business.industry ,Neurodegeneration ,Parkinson Disease ,General Medicine ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,030220 oncology & carcinogenesis ,alpha-Synuclein ,biological phenomena, cell phenomena, and immunity ,business ,Protein Processing, Post-Translational ,Neuroscience ,Research Article - 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 (αSyn(Agg)) 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.
- Published
- 2020
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