Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment

Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment

The potassium sodium-activated channel subtype T member 1 (<i>KCNT1</i>) gene encodes the Slack channel K<sub>Na</sub>1.1, which is expressed in neurons throughout the brain. Gain-of-function variants in <i>KCNT1</i> are associated with a spectrum of epilepsy synd...

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Main Authors: Fangxu Sun, Huafeng Wang, Jing Wu, Imran H. Quraishi, Yalan Zhang, Maysam Pedram, Benbo Gao, Elizabeth A. Jonas, Viet Nguyen, Sijia Wu, Omar S. Mabrouk, Paymaan Jafar-nejad, Leonard K. Kaczmarek
Format: Article
Language:English
Published: MDPI AG 2024-11-01
Series:Biomolecules
Subjects:
slack
KCNT1
K<sub>Na</sub>1.1
epilepsy
intellectual disability
EIMFS
Online Access:https://www.mdpi.com/2218-273X/14/11/1397
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Summary:The potassium sodium-activated channel subtype T member 1 (<i>KCNT1</i>) gene encodes the Slack channel K<sub>Na</sub>1.1, which is expressed in neurons throughout the brain. Gain-of-function variants in <i>KCNT1</i> are associated with a spectrum of epilepsy syndromes, and mice carrying those variants exhibit a robust phenotype similar to that observed in patients. <i>Kcnt1</i> knockout (KO) mice, however, have a normal lifespan without any epileptic phenotype. To understand the molecular differences between these two models, we conducted a comprehensive proteomic analysis of the cerebral cortices of <i>Kcnt1</i> KO and <i>Kcnt1</i><sup>R455H/+</sup> mice, an animal model bearing a cytoplasmic C-terminal mutation homologous to a human R474H variant that results in EIMFS. The greatest change observed in <i>Kcnt1</i> KO mice compared to the wild-type mice was the increased expression of multiple proteins of the inner mitochondrial membrane. Electron microscopy studies of cortical mitochondria from <i>Kcnt1</i> KO mice further confirmed a significant increase in the density of mitochondrial cristae compared to that in wild-type mice. <i>Kcnt1</i> reduction by a murine-specific <i>Kcnt1</i> antisense oligonucleotide (ASO) in <i>Kcnt1</i><sup>R455H/+</sup> mice partially corrected the proteomic dysregulations in the disease model. The results support the hypothesis that ASO-mediated <i>KCNT1</i> reduction could be therapeutically useful in the treatment of <i>KCNT1</i> epilepsies.
ISSN:2218-273X

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