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Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from a point mutation at the 5’ splice site of intron 20 in the IKBKAP gene. This mutation decreases production of the IKAP protein, and treatments that increase the level of the full-length IKBKAP transcript are...

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Autores principales: Yannai, Sivan, Zonszain, Jonathan, Donyo, Maya, Ast, Gil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424424/
https://www.ncbi.nlm.nih.gov/pubmed/30889183
http://dx.doi.org/10.1371/journal.pone.0211602
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author Yannai, Sivan
Zonszain, Jonathan
Donyo, Maya
Ast, Gil
author_facet Yannai, Sivan
Zonszain, Jonathan
Donyo, Maya
Ast, Gil
author_sort Yannai, Sivan
collection PubMed
description Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from a point mutation at the 5’ splice site of intron 20 in the IKBKAP gene. This mutation decreases production of the IKAP protein, and treatments that increase the level of the full-length IKBKAP transcript are likely to be of therapeutic value. We previously found that phosphatidylserine (PS), an FDA-approved food supplement, elevates IKAP levels in cells generated from FD patients. Here we demonstrate that combined treatment of cells generated from FD patients with PS and kinetin or PS and the histone deacetylase inhibitor trichostatin A (TSA) resulted in an additive elevation of IKAP compared to each drug alone. This indicates that the compounds influence different pathways. We also found that pridopidine enhances production of IKAP in cells generated from FD patients. Pridopidine has an additive effect on IKAP levels when used in combination with kinetin or TSA, but not with PS; suggesting that PS and pridopidine influence IKBKAP levels through the same mechanism. Indeed, we demonstrate that the effect of PS and pridopidine is through sigma-1 receptor-mediated activation of the BDNF signaling pathway. A combination treatment with any of these drugs with different mechanisms has potential to benefit FD patients.
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spelling pubmed-64244242019-04-02 Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients Yannai, Sivan Zonszain, Jonathan Donyo, Maya Ast, Gil PLoS One Research Article Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from a point mutation at the 5’ splice site of intron 20 in the IKBKAP gene. This mutation decreases production of the IKAP protein, and treatments that increase the level of the full-length IKBKAP transcript are likely to be of therapeutic value. We previously found that phosphatidylserine (PS), an FDA-approved food supplement, elevates IKAP levels in cells generated from FD patients. Here we demonstrate that combined treatment of cells generated from FD patients with PS and kinetin or PS and the histone deacetylase inhibitor trichostatin A (TSA) resulted in an additive elevation of IKAP compared to each drug alone. This indicates that the compounds influence different pathways. We also found that pridopidine enhances production of IKAP in cells generated from FD patients. Pridopidine has an additive effect on IKAP levels when used in combination with kinetin or TSA, but not with PS; suggesting that PS and pridopidine influence IKBKAP levels through the same mechanism. Indeed, we demonstrate that the effect of PS and pridopidine is through sigma-1 receptor-mediated activation of the BDNF signaling pathway. A combination treatment with any of these drugs with different mechanisms has potential to benefit FD patients. Public Library of Science 2019-03-19 /pmc/articles/PMC6424424/ /pubmed/30889183 http://dx.doi.org/10.1371/journal.pone.0211602 Text en © 2019 Yannai et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Yannai, Sivan
Zonszain, Jonathan
Donyo, Maya
Ast, Gil
Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients
title Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients
title_full Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients
title_fullStr Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients
title_full_unstemmed Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients
title_short Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients
title_sort combinatorial treatment increases ikap levels in human cells generated from familial dysautonomia patients
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424424/
https://www.ncbi.nlm.nih.gov/pubmed/30889183
http://dx.doi.org/10.1371/journal.pone.0211602
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