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Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson’s disease
Souvarish Sarkar, … , Heike Wulff, Anumantha G. Kanthasamy
Souvarish Sarkar, … , Heike Wulff, Anumantha G. Kanthasamy
Published June 29, 2020
Citation Information: J Clin Invest. 2020;130(8):4195-4212. https://doi.org/10.1172/JCI136174.
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Research Article Inflammation Neuroscience Article has an altmetric score of 24

Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson’s disease

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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.

Authors

Souvarish Sarkar, Hai M. Nguyen, Emir Malovic, Jie Luo, Monica Langley, Bharathi N. Palanisamy, Neeraj Singh, Sireesha Manne, Matthew Neal, Michelle Gabrielle, Ahmed Abdalla, Poojya Anantharam, Dharmin Rokad, Nikhil Panicker, Vikrant Singh, Muhammet Ay, Adhithiya Charli, Dilshan Harischandra, Lee-Way Jin, Huajun Jin, Srikant Rangaraju, Vellareddy Anantharam, Heike Wulff, Anumantha G. Kanthasamy

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Figure 7

PAP-1 reduces inflammation and neurodegeneration in mouse models of PD.

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PAP-1 reduces inflammation and neurodegeneration in mouse models of PD.
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(A–H) MitoPark mouse model. (A) Representative movement tracks showing that PAP-1 rescued movement deficits of MitoPark mice at 20 weeks. (B) VersaMax open-field test showed increased horizontal activity of MitoPark mice treated with PAP-1 compared with the vehicle-treated control group. (C) Behavior test revealed increased time spent on the rotarod by MitoPark mice treated with PAP-1 compared with the vehicle-treated group. (D–F) HPLC showing that PAP-1 treatment protected MitoPark mice from loss of (D) dopamine (DA), (E) DOPAC, and (F) HVA. (G) IHC of SNpc showing that PAP-1 protected against loss of TH-positive neurons in MitoPark mice and stereology analysis of the SNpc showing that PAP-1 decreased the loss of TH-positive neurons in MitoPark mice. Scale bars: 200 μm (top panel); 100 μm (bottom panel). (H–L) MPTP mouse model. (H) IHC of MPTP-exposed substantia nigra and striatum showing that PAP-1 altered microgliosis. Scale bars: 50 μm (top panel); 20 μm (insets); 100 μm (bottom panel). (I) ImageJ analysis of MPTP-exposed substantia nigra showing that PAP-1 reduced soma size and increased the number of microglial branches. (J) qRT-PCR analysis of striatum after MPTP showing reduced mRNA expression of proinflammatory factors IL-1β and TNF-α. (K) IHC of SNpc showing that PAP-1 protected against MPTP-induced loss of TH-positive neurons. Scale bars: 500 μm (top panel); 200 μm (bottom panel). (L) Stereological analysis of the SNpc showing that PAP-1 decreased the loss of TH-positive neurons after MPTP treatment. One-way ANOVA was used to compare multiple groups. In most cases, Tukey’s post hoc analysis was applied. Each dot on the bar graphs represents a biological replicate. Data are presented as the mean ± SEM, with 3–7 animals per group. *P ≤ 0.05, **P < 0.01, and ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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