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The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models

Friedreich’s ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the prop...

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Autores principales: Llorens, José Vicente, Soriano, Sirena, Calap-Quintana, Pablo, Gonzalez-Cabo, Pilar, Moltó, María Dolores
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387962/
https://www.ncbi.nlm.nih.gov/pubmed/30833885
http://dx.doi.org/10.3389/fnins.2019.00075
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author Llorens, José Vicente
Soriano, Sirena
Calap-Quintana, Pablo
Gonzalez-Cabo, Pilar
Moltó, María Dolores
author_facet Llorens, José Vicente
Soriano, Sirena
Calap-Quintana, Pablo
Gonzalez-Cabo, Pilar
Moltó, María Dolores
author_sort Llorens, José Vicente
collection PubMed
description Friedreich’s ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the proprioceptive pathways in the spinal cord, peripheral nerves and nuclei of the cerebellum. FRDA is an inherited disease with an autosomal recessive pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, which is an essential and highly evolutionary conserved protein whose deficit results in iron metabolism dysregulation and mitochondrial dysfunction. The first experimental evidence connecting frataxin with iron homeostasis came from Saccharomyces cerevisiae; iron accumulates in the mitochondria of yeast with deletion of the frataxin ortholog gene. This finding was soon linked to previous observations of iron deposits in the hearts of FRDA patients and was later reported in animal models of the disease. Despite advances made in the understanding of FRDA pathophysiology, the role of iron in this disease has not yet been completely clarified. Some of the questions still unresolved include the molecular mechanisms responsible for the iron accumulation and iron-mediated toxicity. Here, we review the contribution of the cellular and animal models of FRDA and relevance of the studies using FRDA patient samples to gain knowledge about these issues. Mechanisms of mitochondrial iron overload are discussed considering the potential roles of frataxin in the major mitochondrial metabolic pathways that use iron. We also analyzed the effect of iron toxicity on neuronal degeneration in FRDA by reactive oxygen species (ROS)-dependent and ROS-independent mechanisms. Finally, therapeutic strategies based on the control of iron toxicity are considered.
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spelling pubmed-63879622019-03-04 The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models Llorens, José Vicente Soriano, Sirena Calap-Quintana, Pablo Gonzalez-Cabo, Pilar Moltó, María Dolores Front Neurosci Neuroscience Friedreich’s ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the proprioceptive pathways in the spinal cord, peripheral nerves and nuclei of the cerebellum. FRDA is an inherited disease with an autosomal recessive pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, which is an essential and highly evolutionary conserved protein whose deficit results in iron metabolism dysregulation and mitochondrial dysfunction. The first experimental evidence connecting frataxin with iron homeostasis came from Saccharomyces cerevisiae; iron accumulates in the mitochondria of yeast with deletion of the frataxin ortholog gene. This finding was soon linked to previous observations of iron deposits in the hearts of FRDA patients and was later reported in animal models of the disease. Despite advances made in the understanding of FRDA pathophysiology, the role of iron in this disease has not yet been completely clarified. Some of the questions still unresolved include the molecular mechanisms responsible for the iron accumulation and iron-mediated toxicity. Here, we review the contribution of the cellular and animal models of FRDA and relevance of the studies using FRDA patient samples to gain knowledge about these issues. Mechanisms of mitochondrial iron overload are discussed considering the potential roles of frataxin in the major mitochondrial metabolic pathways that use iron. We also analyzed the effect of iron toxicity on neuronal degeneration in FRDA by reactive oxygen species (ROS)-dependent and ROS-independent mechanisms. Finally, therapeutic strategies based on the control of iron toxicity are considered. Frontiers Media S.A. 2019-02-18 /pmc/articles/PMC6387962/ /pubmed/30833885 http://dx.doi.org/10.3389/fnins.2019.00075 Text en Copyright © 2019 Llorens, Soriano, Calap-Quintana, Gonzalez-Cabo and Moltó. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Llorens, José Vicente
Soriano, Sirena
Calap-Quintana, Pablo
Gonzalez-Cabo, Pilar
Moltó, María Dolores
The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models
title The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models
title_full The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models
title_fullStr The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models
title_full_unstemmed The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models
title_short The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models
title_sort role of iron in friedreich’s ataxia: insights from studies in human tissues and cellular and animal models
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387962/
https://www.ncbi.nlm.nih.gov/pubmed/30833885
http://dx.doi.org/10.3389/fnins.2019.00075
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