TY - JOUR
T1 - Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson’s disease
AU - Sarkar, Souvarish
AU - Nguyen, Hai M.
AU - Malovic, Emir
AU - Luo, Jie
AU - Langley, Monica
AU - Palanisamy, Bharathi N.
AU - Singh, Neeraj
AU - Manne, Sireesha
AU - Neal, Matthew
AU - Gabrielle, Michelle
AU - Abdalla, Ahmed
AU - Anantharam, Poojya
AU - Rokad, Dharmin
AU - Panicker, Nikhil
AU - Singh, Vikrant
AU - Ay, Muhammet
AU - Charli, Adhithiya
AU - Harischandra, Dilshan
AU - Jin, Lee Way
AU - Jin, Huajun
AU - Rangaraju, Srikant
AU - Anantharam, Vellareddy
AU - Wulff, Heike
AU - Kanthasamy, Anumantha G.
PY - 2020/8/3
Y1 - 2020/8/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI136174
DO - 10.1172/JCI136174
M3 - Article
C2 - 32597830
AN - SCOPUS:85087945152
VL - 140
SP - 4195
EP - 4212
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 8
ER -