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Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration

Mutations in Frataxin (FXN) cause Friedreich’s ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS ind...

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Autores principales: Chen, Kuchuan, Lin, Guang, Haelterman, Nele A, Ho, Tammy Szu-Yu, Li, Tongchao, Li, Zhihong, Duraine, Lita, Graham, Brett H, Jaiswal, Manish, Yamamoto, Shinya, Rasband, Matthew N, Bellen, Hugo J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956409/
https://www.ncbi.nlm.nih.gov/pubmed/27343351
http://dx.doi.org/10.7554/eLife.16043
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author Chen, Kuchuan
Lin, Guang
Haelterman, Nele A
Ho, Tammy Szu-Yu
Li, Tongchao
Li, Zhihong
Duraine, Lita
Graham, Brett H
Jaiswal, Manish
Yamamoto, Shinya
Rasband, Matthew N
Bellen, Hugo J
author_facet Chen, Kuchuan
Lin, Guang
Haelterman, Nele A
Ho, Tammy Szu-Yu
Li, Tongchao
Li, Zhihong
Duraine, Lita
Graham, Brett H
Jaiswal, Manish
Yamamoto, Shinya
Rasband, Matthew N
Bellen, Hugo J
author_sort Chen, Kuchuan
collection PubMed
description Mutations in Frataxin (FXN) cause Friedreich’s ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA. DOI: http://dx.doi.org/10.7554/eLife.16043.001
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spelling pubmed-49564092016-07-28 Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration Chen, Kuchuan Lin, Guang Haelterman, Nele A Ho, Tammy Szu-Yu Li, Tongchao Li, Zhihong Duraine, Lita Graham, Brett H Jaiswal, Manish Yamamoto, Shinya Rasband, Matthew N Bellen, Hugo J eLife Neuroscience Mutations in Frataxin (FXN) cause Friedreich’s ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA. DOI: http://dx.doi.org/10.7554/eLife.16043.001 eLife Sciences Publications, Ltd 2016-06-25 /pmc/articles/PMC4956409/ /pubmed/27343351 http://dx.doi.org/10.7554/eLife.16043 Text en © 2016, Chen et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Chen, Kuchuan
Lin, Guang
Haelterman, Nele A
Ho, Tammy Szu-Yu
Li, Tongchao
Li, Zhihong
Duraine, Lita
Graham, Brett H
Jaiswal, Manish
Yamamoto, Shinya
Rasband, Matthew N
Bellen, Hugo J
Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration
title Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration
title_full Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration
title_fullStr Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration
title_full_unstemmed Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration
title_short Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration
title_sort loss of frataxin induces iron toxicity, sphingolipid synthesis, and pdk1/mef2 activation, leading to neurodegeneration
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956409/
https://www.ncbi.nlm.nih.gov/pubmed/27343351
http://dx.doi.org/10.7554/eLife.16043
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