Article detail · 2020
Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson’s disease
- Year
- 2020
- Type
- article
Data source split
- YÖKSİS YÖKSİS article record
- YÖKSİS venue JOURNAL OF CLINICAL INVESTIGATION
- Catalog match (ISSN) Journal of Clinical Investigation
- OpenAlex OpenAlex enrichment (abstract, citations, topics)
Abstract
OpenAlex · English
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.
Topics
Citations
OpenAlex cited_by_count. Not a WoS or Scopus citation count; those sources have no separate column here.
116 citations
OpenAlex cited_by_count (cache / database)
2 publications in the local catalog that cite this work (OpenAlex reference match; not the full global list).