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Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease

Charcot–Marie–Tooth (CMT) disease is a neuropathy that lacks effective therapy. CMT patients show degeneration of peripheral nerves, leading to muscle weakness and loss of proprioception. Loss of mitochondrial oxidative phosphorylation proteins and enzymes of the antioxidant response accompany degen...

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Autores principales: Nuevo-Tapioles, Cristina, Santacatterina, Fulvio, Sánchez-Garrido, Brenda, de Arenas, Cristina Núñez, Robledo-Bérgamo, Adrián, Martínez-Valero, Paula, Cantarero, Lara, Pardo, Beatriz, Hoenicka, Janet, Murphy, Michael P, Satrústegui, Jorgina, Palau, Francesc, Cuezva, José M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643506/
https://www.ncbi.nlm.nih.gov/pubmed/34274972
http://dx.doi.org/10.1093/hmg/ddab207
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author Nuevo-Tapioles, Cristina
Santacatterina, Fulvio
Sánchez-Garrido, Brenda
de Arenas, Cristina Núñez
Robledo-Bérgamo, Adrián
Martínez-Valero, Paula
Cantarero, Lara
Pardo, Beatriz
Hoenicka, Janet
Murphy, Michael P
Satrústegui, Jorgina
Palau, Francesc
Cuezva, José M
author_facet Nuevo-Tapioles, Cristina
Santacatterina, Fulvio
Sánchez-Garrido, Brenda
de Arenas, Cristina Núñez
Robledo-Bérgamo, Adrián
Martínez-Valero, Paula
Cantarero, Lara
Pardo, Beatriz
Hoenicka, Janet
Murphy, Michael P
Satrústegui, Jorgina
Palau, Francesc
Cuezva, José M
author_sort Nuevo-Tapioles, Cristina
collection PubMed
description Charcot–Marie–Tooth (CMT) disease is a neuropathy that lacks effective therapy. CMT patients show degeneration of peripheral nerves, leading to muscle weakness and loss of proprioception. Loss of mitochondrial oxidative phosphorylation proteins and enzymes of the antioxidant response accompany degeneration of nerves in skin biopsies of CMT patients. Herein, we followed a drug-repurposing approach to find drugs in a Food and Drug Administration-approved library that could prevent development of CMT disease in the Gdap1-null mouse model. We found that the antibiotic florfenicol is a mitochondrial uncoupler that prevents the production of reactive oxygen species and activates respiration in human GDAP1-knockdown neuroblastoma cells and in dorsal root ganglion neurons of Gdap1-null mice. Treatment of CMT-affected Gdap1-null mice with florfenicol has no beneficial effect in the course of the disease. However, administration of florfenicol, or the antioxidant MitoQ, to pre-symptomatic GDAP1-null mice prevented weight gain and ameliorated the motor coordination deficiencies that developed in the Gdap1-null mice. Interestingly, both florfenicol and MitoQ halted the decay in mitochondrial and redox proteins in sciatic nerves of Gdap1-null mice, supporting that oxidative damage is implicated in the etiology of the neuropathy. These findings support the development of clinical trials for translation of these drugs for treatment of CMT patients.
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spelling pubmed-86435062021-12-06 Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease Nuevo-Tapioles, Cristina Santacatterina, Fulvio Sánchez-Garrido, Brenda de Arenas, Cristina Núñez Robledo-Bérgamo, Adrián Martínez-Valero, Paula Cantarero, Lara Pardo, Beatriz Hoenicka, Janet Murphy, Michael P Satrústegui, Jorgina Palau, Francesc Cuezva, José M Hum Mol Genet General Article Charcot–Marie–Tooth (CMT) disease is a neuropathy that lacks effective therapy. CMT patients show degeneration of peripheral nerves, leading to muscle weakness and loss of proprioception. Loss of mitochondrial oxidative phosphorylation proteins and enzymes of the antioxidant response accompany degeneration of nerves in skin biopsies of CMT patients. Herein, we followed a drug-repurposing approach to find drugs in a Food and Drug Administration-approved library that could prevent development of CMT disease in the Gdap1-null mouse model. We found that the antibiotic florfenicol is a mitochondrial uncoupler that prevents the production of reactive oxygen species and activates respiration in human GDAP1-knockdown neuroblastoma cells and in dorsal root ganglion neurons of Gdap1-null mice. Treatment of CMT-affected Gdap1-null mice with florfenicol has no beneficial effect in the course of the disease. However, administration of florfenicol, or the antioxidant MitoQ, to pre-symptomatic GDAP1-null mice prevented weight gain and ameliorated the motor coordination deficiencies that developed in the Gdap1-null mice. Interestingly, both florfenicol and MitoQ halted the decay in mitochondrial and redox proteins in sciatic nerves of Gdap1-null mice, supporting that oxidative damage is implicated in the etiology of the neuropathy. These findings support the development of clinical trials for translation of these drugs for treatment of CMT patients. Oxford University Press 2021-07-19 /pmc/articles/PMC8643506/ /pubmed/34274972 http://dx.doi.org/10.1093/hmg/ddab207 Text en © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle General Article
Nuevo-Tapioles, Cristina
Santacatterina, Fulvio
Sánchez-Garrido, Brenda
de Arenas, Cristina Núñez
Robledo-Bérgamo, Adrián
Martínez-Valero, Paula
Cantarero, Lara
Pardo, Beatriz
Hoenicka, Janet
Murphy, Michael P
Satrústegui, Jorgina
Palau, Francesc
Cuezva, José M
Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease
title Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease
title_full Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease
title_fullStr Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease
title_full_unstemmed Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease
title_short Effective therapeutic strategies in a preclinical mouse model of Charcot–Marie–Tooth disease
title_sort effective therapeutic strategies in a preclinical mouse model of charcot–marie–tooth disease
topic General Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643506/
https://www.ncbi.nlm.nih.gov/pubmed/34274972
http://dx.doi.org/10.1093/hmg/ddab207
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