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Indelicato E, Delatycki MB, Farmer J, França MC, Perlman S, Rai M, Boesch S. A global perspective on research advances and future challenges in Friedreich ataxia. Nat Rev Neurol 2025; 21:204-215. [PMID: 40032987 DOI: 10.1038/s41582-025-01065-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2025] [Indexed: 03/05/2025]
Abstract
Friedreich ataxia (FRDA) is a rare multisystem, life-limiting disease and is the most common early-onset inherited ataxia in populations of European, Arab and Indian descent. In recent years, substantial progress has been made in dissecting the pathogenesis and natural history of FRDA, and several clinical trials have been initiated. A particularly notable recent achievement was the approval of the nuclear factor erythroid 2-related factor 2 activator omaveloxolone as the first disease-specific therapy for FRDA. In light of these developments, we review milestones in FRDA translational and clinical research over the past 10 years, as well as the various therapeutic strategies currently in the pipeline. We also consider the lessons that have been learned from failed trials and other setbacks. We conclude by presenting a global roadmap for future research, as outlined by the recently established Friedreich's Ataxia Global Clinical Consortium, which covers North and South America, Europe, India, Australia and New Zealand.
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Affiliation(s)
- Elisabetta Indelicato
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | | | | | | | - Myriam Rai
- Friedreich's Ataxia Research Alliance, Downingtown, PA, USA
- Laboratory of Experimental Neurology, Brussels, Belgium
| | - Sylvia Boesch
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
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Ercanbrack WS, Ramirez M, Dungan A, Gaul E, Ercanbrack SJ, Wingert RA. Frataxin deficiency and the pathology of Friedreich's Ataxia across tissues. Tissue Barriers 2025:2462357. [PMID: 39981684 DOI: 10.1080/21688370.2025.2462357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 01/08/2025] [Accepted: 01/14/2025] [Indexed: 02/22/2025] Open
Abstract
Friedreich's Ataxia (FRDA) is a neurodegenerative disease that affects a variety of different organ systems. The disease is caused by GAA repeat expansions in intron 1 of the Frataxin gene (FXN), which results in a decrease in the expression of the FXN protein. FXN is needed for the biogenesis of iron-sulfur clusters (ISC) which are required by key metabolic processes in the mitochondria. Without ISCs those processes do not occur properly. As a result, reactive oxygen species accumulate, and the mitochondria cease to function. Iron is also thought to accumulate in the cells of certain tissue types. These processes are thought to be intimately related to the pathologies affecting a myriad of tissues in FRDA. Most FRDA patients suffer from loss of motor control, cardiomyopathy, scoliosis, foot deformities, and diabetes. In this review, we discuss the known features of FRDA pathology and the current understanding about the basis of these alterations.
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Affiliation(s)
- Wesley S Ercanbrack
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Mateo Ramirez
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Austin Dungan
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Ella Gaul
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Sarah J Ercanbrack
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Rebecca A Wingert
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
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Wu L, Huang F, Yang L, Yang L, Sun Z, Zhang J, Xia S, Zhao H, Ding Y, Bian D, Li K. Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich's ataxia mouse model. Sci Rep 2024; 14:19876. [PMID: 39191875 DOI: 10.1038/s41598-024-71099-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/23/2024] [Indexed: 08/29/2024] Open
Abstract
Frataxin (FXN) is required for iron-sulfur cluster biogenesis, and its loss causes the early-onset neurodegenerative disease Friedreich ataxia (FRDA). Loss of FXN is a susceptibility factor in the development of diabetes, a common metabolic complication after myocardial hypertrophy in patients with FRDA. The underlying mechanism of FXN deficient-induced hyperglycemia in FRDA is, however, poorly understood. In this study, we confirmed that the FXN deficiency mouse model YG8R develops insulin resistance in elder individuals by disturbing lipid metabolic homeostasis in adipose tissues. Evaluation of lipolysis, lipogenesis, and fatty acid β-oxidation showed that lipolysis is most severely affected in white adipose tissues. Consistently, FXN deficiency significantly decreased expression of lipolytic genes encoding adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) resulting in adipocyte enlargement and inflammation. Lipolysis induction by fasting or cold exposure remarkably upregulated FXN expression, though FXN deficiency lessened the competency of lipolysis compared with the control or wild type mice. Moreover, we found that the impairment of lipolysis was present at a young age, a few months earlier than hyperglycemia and insulin resistance. Forskolin, an activator of lipolysis, or pioglitazone, an agonist of PPARγ, improved insulin sensitivity in FXN-deficient adipocytes or mice. We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.
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Affiliation(s)
- Lin Wu
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Fei Huang
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China
| | - Lu Yang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Liu Yang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Zichen Sun
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Jinghua Zhang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Siyu Xia
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China
| | - Hongting Zhao
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Yibing Ding
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Dezhi Bian
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China.
| | - Kuanyu Li
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.
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Wu L, Huang F, Sun Z, Zhang J, Xia S, Zhao H, Liu Y, Yang L, Ding Y, Bian D, Li K, Sun Y. Downregulation of Iron-Sulfur Cluster Biogenesis May Contribute to Hyperglycemia-Mediated Diabetic Peripheral Neuropathy in Murine Models. Antioxidants (Basel) 2024; 13:1036. [PMID: 39334695 PMCID: PMC11446412 DOI: 10.3390/antiox13091036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/06/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is considered one of the most common chronic complications of diabetes. Impairment of mitochondrial function is regarded as one of the causes. Iron-sulfur clusters are essential cofactors for numerous iron-sulfur (Fe-S)-containing proteins/enzymes, including mitochondrial electron transport chain complex I, II, and III and aconitase. METHODS To determine the impact of hyperglycemia on peripheral nerves, we used Schwann-like RSC96 cells and classical db/db mice to detect the expression of Fe-S-related proteins, mitochondrially enzymatic activities, and iron metabolism. Subsequently, we treated high-glucose-induced RSC96 cells and db/db mice with pioglitazone (PGZ), respectively, to evaluate the effects on Fe-S cluster biogenesis, mitochondrial function, and animal behavior. RESULTS We found that the core components of Fe-S biogenesis machinery, such as frataxin (Fxn) and scaffold protein IscU, significantly decreased in high-glucose-induced RSC96 cells and db/db mice, accompanied by compromised mitochondrial Fe-S-containing enzymatic activities, such as complex I and II and aconitase. Consequently, oxidative stress and inflammation increased. PGZ not only has antidiabetic effects but also increases the expression of Fxn and IscU to enhance mitochondrial function in RSC96 cells and db/db mice. Meanwhile, PGZ significantly alleviated sciatic nerve injury and improved peripheral neuronal behavior, accompanied by suppressed oxidative stress and inflammation in the sciatic nerve of the db/db mice. CONCLUSIONS Iron-sulfur cluster deficiency may contribute to hyperglycemia-mediated DPN.
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Affiliation(s)
- Lin Wu
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Fei Huang
- Endocrinology Department, Yancheng First People’s Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng 224000, China
| | - Zichen Sun
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Jinghua Zhang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Siyu Xia
- Endocrinology Department, Yancheng First People’s Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng 224000, China
| | - Hongting Zhao
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Yutong Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Vascular Surgery, Nanjing Drum Tower Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
| | - Lu Yang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Yibing Ding
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Dezhi Bian
- Endocrinology Department, Yancheng First People’s Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng 224000, China
| | - Kuanyu Li
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
- Suqian Scientific Research Institute of Nanjing University Medical School, Nanjing University, Suqian 223800, China
| | - Yu Sun
- Suqian Scientific Research Institute of Nanjing University Medical School, Nanjing University, Suqian 223800, China
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Molenaars M, Mir H, Alvarez SW, Arivazhagan L, Rosselot C, Zhan D, Park CY, Garcia-Ocana A, Schmidt AM, Possemato R. Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.19.608291. [PMID: 39229169 PMCID: PMC11370322 DOI: 10.1101/2024.08.19.608291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Iron-sulfur clusters (ISCs) are cell-essential cofactors present in ∼60 proteins including subunits of OXPHOS complexes I-III, DNA polymerases, and iron-sensing proteins. Dysfunctions in ISC biosynthesis are associated with anemias, neurodegenerative disorders, and metabolic diseases. To assess consequences of acute ISC inhibition in a whole body setting, we developed a mouse model in which key ISC biosynthetic enzyme NFS1 can be acutely and reversibly suppressed. Contrary to in vitro ISC inhibition and pharmacological OXPHOS suppression, global NFS1 inhibition rapidly enhances lipid utilization and decreases adiposity without affecting caloric intake and physical activity. ISC proteins decrease, including key proteins involved in OXPHOS (SDHB), lipoic acid synthesis (LIAS), and insulin mRNA processing (CDKAL1), causing acute metabolic inflexibility. Age-related metabolic changes decelerate loss of adiposity substantially prolonged survival of mice with NFS1 inhibition. Thus, the observation that ISC metabolism impacts organismal fuel choice will aid in understanding the mechanisms underlying ISC diseases with increased risk for diabetes. Graphical abstract Highlights Acute ISC inhibition leads to rapid loss of adiposity in miceMulti-metabolic pathway disruption upon ISC deficiency blocks energy storageNfs1 inhibition induces glucose dyshomeostasis due to ISC deficiency in β-cellsEnergy distress caused by inhibition of ISC synthesis is attenuated in aged mice.
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Vancheri C, Quatrana A, Morini E, Mariotti C, Mongelli A, Fichera M, Rufini A, Condò I, Testi R, Novelli G, Malisan F, Amati F. An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease. Hum Genomics 2024; 18:50. [PMID: 38778374 PMCID: PMC11110315 DOI: 10.1186/s40246-024-00602-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 03/26/2024] [Indexed: 05/25/2024] Open
Abstract
Friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the Caucasian population. A unique therapeutic drug for FRDA, the antioxidant Omaveloxolone, has been recently approved by the US Food and Drug Administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. Cardiomyopathy is the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. We conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. Among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. The analysis of the Receiver Operating Characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an Area Under the Curve (AUC) of 0.86 (95%, Confidence Interval 0.77-0.95; p-value < 0.0001). An in silico prediction analysis indicated that the IL6ST gene, an interesting marker of neuroinflammation in FRDA, is a common target gene of both miRNAs. Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients' group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology.
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Affiliation(s)
- Chiara Vancheri
- Department of Biomedicine and Prevention, Genetics Unit, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
| | - Andrea Quatrana
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
- Muscular and Neurodegenerative Diseases Laboratory, Bambino Gesù, Children's Hospital, IRCCS, Rome, Italy
| | - Elena Morini
- Department of Biomedicine and Prevention, Genetics Unit, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
| | - Caterina Mariotti
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20133, Italy
| | - Alessia Mongelli
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20133, Italy
| | - Mario Fichera
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20133, Italy
| | - Alessandra Rufini
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
- Saint Camillus International University of Health and Medical Sciences, Rome, 00131, Italy
| | - Ivano Condò
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
| | - Roberto Testi
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, Genetics Unit, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
- Neuromed Institute, IRCCS, Pozzilli, 86077, Italy
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV, 89557, USA
| | - Florence Malisan
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy.
| | - Francesca Amati
- Department of Biomedicine and Prevention, Genetics Unit, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy.
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Indelicato E, Reetz K, Maier S, Nachbauer W, Amprosi M, Giunti P, Mariotti C, Durr A, de Rivera Garrido FJR, Klopstock T, Schöls L, Klockgether T, Bürk K, Pandolfo M, Didszun C, Grobe-Einsler M, Nanetti L, Nenning L, Kiechl S, Dichtl W, Ulmer H, Schulz JB, Boesch S. Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study. Mov Disord 2024; 39:510-518. [PMID: 38140802 DOI: 10.1002/mds.29687] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/24/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Friedreich's ataxia (FA) is a rare multisystemic disorder which can cause premature death. OBJECTIVES To investigate predictors of survival in FA. METHODS Within a prospective registry established by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; ClinicalTrials.gov identifier NCT02069509) we enrolled genetically confirmed FA patients at 11 tertiary centers and followed them in yearly intervals. We investigated overall survival applying the Kaplan-Meier method, life tables, and log-rank test. We explored prognostic factors applying Cox proportional hazards regression and subsequently built a risk score which was assessed for discrimination and calibration performance. RESULTS Between September 2010 and March 2017, we enrolled 631 FA patients. Median age at inclusion was 31 (range, 6-76) years. Until December 2022, 44 patients died and 119 terminated the study for other reasons. The 10-year cumulative survival rate was 87%. In a multivariable analysis, the disability stage (hazard ratio [HR] 1.51, 95% CI 1.08-2.12, P = 0.02), history of arrhythmic disorder (HR 2.93, 95% CI 1.34-6.39, P = 0.007), and diabetes mellitus (HR 2.31, 95% CI 1.05-5.10, P = 0.04) were independent predictors of survival. GAA repeat lengths did not improve the survival model. A risk score built on the previously described factors plus the presence of left ventricular systolic dysfunction at echocardiography enabled identification of four trajectories to prognosticate up to 10-year survival (log-rank test P < 0.001). CONCLUSIONS Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Elisabetta Indelicato
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
| | - Kathrin Reetz
- Department of Neurology, RWTH Aachen University, Aachen, Germany
- JARA-BRAIN Institute of Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany
| | - Sarah Maier
- Institute of Medical Statistics and Informatics, Medical University Innsbruck, Innsbruck, Austria
| | - Wolfgang Nachbauer
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
| | - Matthias Amprosi
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
| | - Paola Giunti
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Caterina Mariotti
- Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Alexandra Durr
- Institut du Cerveau et de la Moelle Epinière, INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris VI UMR S1127, Paris, France
- APHP, Genetics Department, Pitié-Salpêtrière University Hospital, Paris, France
| | - Francisco J R de Rivera Garrido
- Reference Unit of Hereditary Ataxias and Paraplegias, Department of Neurology, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
| | - Thomas Klopstock
- Department of Neurology with Friedrich-Baur-Institute, University of Munich, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Ludger Schöls
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - Thomas Klockgether
- Department of Neurology, University Hospital of Bonn, Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Katrin Bürk
- Department of Neurology, Philipps University of Marburg, Marburg, Germany
| | - Massimo Pandolfo
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
| | - Claire Didszun
- Department of Neurology, RWTH Aachen University, Aachen, Germany
- JARA-BRAIN Institute of Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany
| | - Marcus Grobe-Einsler
- Department of Neurology, University Hospital of Bonn, Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Lorenzo Nanetti
- Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Lukas Nenning
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
| | - Stefan Kiechl
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
- VASCage, Centre on Clinical Stroke Research, Innsbruck, Austria
| | - Wolfgang Dichtl
- Department of Internal Medicine III (Cardiology and Angiology), Medical University Innsbruck, Innsbruck, Austria
| | - Hanno Ulmer
- Institute of Medical Statistics and Informatics, Medical University Innsbruck, Innsbruck, Austria
| | - Jörg B Schulz
- Department of Neurology, RWTH Aachen University, Aachen, Germany
- JARA-BRAIN Institute of Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany
| | - Sylvia Boesch
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
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Turchi R, Sciarretta F, Ceci V, Tiberi M, Audano M, Pedretti S, Panebianco C, Nesci V, Pazienza V, Ferri A, Carotti S, Chiurchiù V, Mitro N, Lettieri-Barbato D, Aquilano K. Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model. iScience 2023; 26:107713. [PMID: 37701569 PMCID: PMC10494209 DOI: 10.1016/j.isci.2023.107713] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/02/2023] [Accepted: 08/23/2023] [Indexed: 09/14/2023] Open
Abstract
Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.
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Affiliation(s)
- Riccardo Turchi
- Department Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - Veronica Ceci
- PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Marta Tiberi
- Laboratory of Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Matteo Audano
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Silvia Pedretti
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Concetta Panebianco
- Gastroenterology Unit Fondazione IRCSS “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG)-Italy
| | - Valentina Nesci
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Division of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Valerio Pazienza
- Gastroenterology Unit Fondazione IRCSS “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG)-Italy
| | - Alberto Ferri
- Division of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy
- Institute of Traslational Pharmacology, IFT-CNR, Rome, Italy
| | - Simone Carotti
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
- Predictive Molecular Diagnostics, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Valerio Chiurchiù
- Laboratory of Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Rome, Italy
- Institute of Traslational Pharmacology, IFT-CNR, Rome, Italy
| | - Nico Mitro
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Daniele Lettieri-Barbato
- Department Biology, University of Rome Tor Vergata, Rome, Italy
- IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Katia Aquilano
- Department Biology, University of Rome Tor Vergata, Rome, Italy
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9
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Maheshwari S, Vilema-Enríquez G, Wade-Martins R. Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application. Transl Neurodegener 2023; 12:45. [PMID: 37726850 PMCID: PMC10510273 DOI: 10.1186/s40035-023-00376-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/28/2023] [Indexed: 09/21/2023] Open
Abstract
Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.
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Affiliation(s)
- Saumya Maheshwari
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
| | - Gabriela Vilema-Enríquez
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
| | - Richard Wade-Martins
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
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10
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Tiberi J, Segatto M, Fiorenza MT, La Rosa P. Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials. Biomedicines 2023; 11:biomedicines11051293. [PMID: 37238963 DOI: 10.3390/biomedicines11051293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/18/2023] [Accepted: 04/22/2023] [Indexed: 05/28/2023] Open
Abstract
Friedreich's ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of FXN gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signalling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signalling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, we overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies.
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Affiliation(s)
- Jessica Tiberi
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
- PhD Program in Behavioral Neuroscience, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
| | - Marco Segatto
- Department of Bioscience and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy
| | - Maria Teresa Fiorenza
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
- European Center for Brain Research, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00179 Rome, Italy
| | - Piergiorgio La Rosa
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
- European Center for Brain Research, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00179 Rome, Italy
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11
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O'Connell TM, Logsdon DL, Payne RM. Metabolomics analysis reveals dysregulation in one carbon metabolism in Friedreich Ataxia. Mol Genet Metab 2022; 136:306-314. [PMID: 35798654 DOI: 10.1016/j.ymgme.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/14/2022] [Accepted: 06/05/2022] [Indexed: 11/30/2022]
Abstract
Friedreich Ataxia (FA) is a rare and often fatal autosomal recessive disease in which a mitochondrial protein, frataxin (FXN), is severely reduced in all tissues. With loss of FXN, mitochondrial metabolism is severely disrupted. Multiple therapeutic approaches are in development, but a key limitation is the lack of biomarkers reflecting the activity of FXN in a timely fashion. We predicted this dysregulated metabolism would present a unique metabolite profile in blood of FA patients versus Controls (Con). Plasma from 10 FA and 11 age and sex matched Con subjects was analyzed by targeted mass spectrometry and untargeted NMR. This combined approach yielded quantitative measurements for 540 metabolites and found 59 unique metabolites (55 from MS and 4 from NMR) that were significantly different between cohorts. Correlation-based network analysis revealed several clusters of pathway related metabolites including a cluster associated with one‑carbon (1C) metabolism composed of formate, sarcosine, hypoxanthine, and homocysteine. Receiver operator characteristics analyses demonstrated an excellent ability to discriminate between Con and FA with AUC values >0.95. These results are the first reported metabolomic analyses of human patients with FA. The metabolic perturbations, especially those related to 1C metabolism, may serve as a valuable biomarker panel of disease progression and response to therapy. The identification of dysregulated 1C metabolism may also inform the search for new therapeutic targets related to this pathway.
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Affiliation(s)
- Thomas M O'Connell
- Department of Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, United States of America; Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States of America; Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States of America.
| | - David L Logsdon
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States of America; Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - R Mark Payne
- Department of Pediatrics, Division of Cardiology, and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States of America
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12
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Payne RM. Cardiovascular Research in Friedreich Ataxia: Unmet Needs and Opportunities. JACC Basic Transl Sci 2022; 7:1267-1283. [PMID: 36644283 PMCID: PMC9831864 DOI: 10.1016/j.jacbts.2022.04.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/18/2022] [Accepted: 04/18/2022] [Indexed: 01/18/2023]
Abstract
Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research.
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Affiliation(s)
- R. Mark Payne
- Address for correspondence: Dr R. Mark Payne, Division of Pediatric Cardiology, Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 West Walnut, R4 302b, Indianapolis, Indiana 46202, USA.
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13
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Tepp K, Aid-Vanakova J, Puurand M, Timohhina N, Reinsalu L, Tein K, Plaas M, Shevchuk I, Terasmaa A, Kaambre T. Wolframin deficiency is accompanied with metabolic inflexibility in rat striated muscles. Biochem Biophys Rep 2022; 30:101250. [PMID: 35295995 PMCID: PMC8918847 DOI: 10.1016/j.bbrep.2022.101250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/28/2022] [Accepted: 03/08/2022] [Indexed: 11/26/2022] Open
Abstract
The protein wolframin is localized in the membrane of the endoplasmic reticulum (ER), influencing Ca2+ metabolism and ER interaction with mitochondria, but the exact role of the protein remains unclear. Mutations in Wfs1 gene cause autosomal recessive disorder Wolfram syndrome (WS). The first symptom of the WS is diabetes mellitus, so accurate diagnosis of the disease as WS is often delayed. In this study we aimed to characterize the role of the Wfs1 deficiency on bioenergetics of muscles. Alterations in the bioenergetic profiles of Wfs1-exon-5-knock-out (Wfs1KO) male rats in comparison with their wild-type male littermates were investigated using high-resolution respirometry, and enzyme activity measurements. The changes were followed in oxidative (cardiac and soleus) and glycolytic (rectus femoris and gastrocnemius) muscles. There were substrate-dependent alterations in the oxygen consumption rate in Wfs1KO rat muscles. In soleus muscle, decrease in respiration rate was significant in all the followed pathways. The relatively small alterations in muscle during development of WS, such as increased mitochondrial content and/or increase in the OxPhos-related enzymatic activity could be an adaptive response to changes in the metabolic environment. The significant decrease in the OxPhos capacity is substrate dependent indicating metabolic inflexibility when multiple substrates are available.
Wolfram syndrome (WS) model rats have muscle type-dependent metabolic changes. Substrate-dependent modulation of OxPhos in WS model rat muscles. Metabolic inflexibility in early-stage WS rat muscle mitochondria.
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14
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Mitochondrial De Novo Assembly of Iron–Sulfur Clusters in Mammals: Complex Matters in a Complex That Matters. INORGANICS 2022. [DOI: 10.3390/inorganics10030031] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/10/2022] Open
Abstract
Iron–sulfur clusters (Fe–S or ISC) are essential cofactors that function in a wide range of biological pathways. In mammalian cells, Fe–S biosynthesis primarily relies on mitochondria and involves a concerted group of evolutionary-conserved proteins forming the ISC pathway. In the early stage of the ISC pathway, the Fe–S core complex is required for de novo assembly of Fe–S. In humans, the Fe–S core complex comprises the cysteine desulfurase NFS1, the scaffold protein ISCU2, frataxin (FXN), the ferredoxin FDX2, and regulatory/accessory proteins ISD11 and Acyl Carrier Protein (ACP). In recent years, the field has made significant advances in unraveling the structure of the Fe–S core complex and the mechanism underlying its function. Herein, we review the key recent findings related to the Fe–S core complex and its components. We highlight some of the unanswered questions and provide a model of the Fe–S assembly within the complex. In addition, we briefly touch on the genetic diseases associated with mutations in the Fe–S core complex components.
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15
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Rufini A, Malisan F, Condò I, Testi R. Drug Repositioning in Friedreich Ataxia. Front Neurosci 2022; 16:814445. [PMID: 35221903 PMCID: PMC8863941 DOI: 10.3389/fnins.2022.814445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/07/2022] [Indexed: 12/14/2022] Open
Abstract
Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It is a severely debilitating disease that significantly impacts the quality of life of affected patients and reduces their life expectancy, however, an adequate cure is not yet available for patients. Frataxin function, although not thoroughly elucidated, is associated with assembly of iron-sulfur cluster and iron metabolism, therefore insufficient frataxin levels lead to reduced activity of many mitochondrial enzymes involved in the electron transport chain, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response. As a consequence, neurons progressively die and patients progressively lose their ability to coordinate movement and perform daily activities. Therapeutic strategies aim at restoring sufficient frataxin levels or at correcting some of the downstream consequences of frataxin deficiency. However, the classical pathways of drug discovery are challenging, require a significant amount of resources and time to reach the final approval, and present a high failure rate. Drug repositioning represents a viable alternative to boost the identification of a therapy, particularly for rare diseases where resources are often limited. In this review we will describe recent efforts aimed at the identification of a therapy for Friedreich ataxia through drug repositioning, and discuss the limitation of such strategies.
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Affiliation(s)
- Alessandra Rufini
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
- Saint Camillus International University of Health and Medical Sciences, Rome, Italy
- *Correspondence: Alessandra Rufini,
| | - Florence Malisan
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Ivano Condò
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Roberto Testi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
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16
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Shah S, Dooms MM, Amaral-Garcia S, Igoillo-Esteve M. Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders. Front Pharmacol 2022; 12:768023. [PMID: 34992533 PMCID: PMC8724568 DOI: 10.3389/fphar.2021.768023] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing–based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington’s disease, Friedreich’s ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.
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Affiliation(s)
- Sweta Shah
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
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17
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Lees JG, Napierala M, Pébay A, Dottori M, Lim SY. Cellular pathophysiology of Friedreich's ataxia cardiomyopathy. Int J Cardiol 2022; 346:71-78. [PMID: 34798207 DOI: 10.1016/j.ijcard.2021.11.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 11/01/2021] [Accepted: 11/12/2021] [Indexed: 12/17/2022]
Abstract
Friedreich's ataxia (FRDA) is a hereditary neuromuscular disorder. Cardiomyopathy is the leading cause of premature death in FRDA. FRDA cardiomyopathy is a complex and progressive disease with no cure or treatment to slow its progression. At the cellular level, cardiomyocyte hypertrophy, apoptosis and fibrosis contribute to the cardiac pathology. However, the heart is composed of multiple cell types and several clinical studies have reported the involvement of cardiac non-myocytes such as vascular cells, autonomic neurons, and inflammatory cells in the pathogenesis of FRDA cardiomyopathy. In fact, several of the cardiac pathologies associated with FRDA including cardiomyocyte necrosis, fibrosis, and arrhythmia, could be contributed to by a diseased vasculature and autonomic dysfunction. Here, we review available evidence regarding the current understanding of cellular mechanisms for, and the involvement of, cardiac non-myocytes in the pathogenesis of FRDA cardiomyopathy.
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Affiliation(s)
- Jarmon G Lees
- O'Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Marek Napierala
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Alice Pébay
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, Victoria 3052, Australia; Department of Surgery, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Mirella Dottori
- Illawarra Health and Medical Research Institute, School of Medicine, Molecular Horizons, University of Wollongong, New South Wales 2522, Australia; Department of Biomedical Engineering, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Shiang Y Lim
- O'Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia; Department of Surgery, The University of Melbourne, Parkville, Victoria 3010, Australia.
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18
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Santos J, Woloski JR, Wu N. Polyuria and Acute Hyperglycemia Secondary to New-Onset Diabetes in a Young Woman With Friedreich's Ataxia. Cureus 2021; 13:e16032. [PMID: 34336519 PMCID: PMC8319161 DOI: 10.7759/cureus.16032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2021] [Indexed: 11/05/2022] Open
Abstract
A 23-year-old woman with progressive Friedreich's ataxia (FRDA) presented to a local urgent care facility for urinary urgency and frequency. A urinalysis showed the presence of trace ketones and glucose, and point-of-care testing revealed severely elevated glucose. The patient was referred to the emergency department and was admitted for further evaluation of hyperglycemia. Laboratory tests were negative for a urinary tract infection; however, results revealed elevated serum glucose and hemoglobin A1C. She was diagnosed with new-onset diabetes mellitus and started on insulin therapy. Management of her diabetes was complicated due to advanced neurodegenerative symptoms related to FRDA. An individualized treatment plan and coordination of care with her home facility were essential for managing her diabetes.
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Affiliation(s)
- Jasmine Santos
- Family Medicine, Geisinger Health System, Geisinger Commonwealth School of Medicine, Wilkes-Barre, USA
| | - Jason R Woloski
- Family Medicine, Geisinger Health System, Geisinger Commonwealth School of Medicine, Wilkes-Barre, USA
| | - Natasha Wu
- Family Medicine, Geisinger Health System, Geisinger Commonwealth School of Medicine, Wilkes-Barre, USA
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19
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Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY. Friedreich Ataxia: Multidisciplinary Clinical Care. J Multidiscip Healthc 2021; 14:1645-1658. [PMID: 34234452 PMCID: PMC8253929 DOI: 10.2147/jmdh.s292945] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/04/2021] [Indexed: 12/17/2022] Open
Abstract
Friedreich ataxia (FRDA) is a multisystem disorder affecting 1 in 50,000-100,000 person in the United States. Traditionally viewed as a neurodegenerative disease, FRDA patients also develop cardiomyopathy, scoliosis, diabetes and other manifestation. Although it usually presents in childhood, it continues throughout life, thus requiring expertise from both pediatric and adult subspecialist in order to provide optimal management. The phenotype of FRDA is unique, giving rise to specific loss of neuronal pathways, a unique form of cardiomyopathy with early hypertrophy and later fibrosis, and diabetes incorporating components of both type I and type II disease. Vision loss, hearing loss, urinary dysfunction and depression also occur in FRDA. Many agents are reaching Phase III trials; if successful, these will provide a variety of new treatments for FRDA that will require many specialists who are not familiar with FRDA to provide clinical therapy. This review provides a summary of the diverse manifestation of FRDA, existing symptomatic therapies, and approaches for integrative care for future therapy in FRDA.
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Affiliation(s)
- David R Lynch
- Division of Neurology, Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Kim Schadt
- Division of Neurology, Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Elizabeth Kichula
- Division of Neurology, Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Shana McCormack
- Division of Endocrinology, Department of Pediatrics, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Kimberly Y Lin
- Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
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20
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Hui CK, Dedkova EN, Montgomery C, Cortopassi G. Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich's ataxia model mice. Hum Mol Genet 2021; 29:3954-3965. [PMID: 33432356 DOI: 10.1093/hmg/ddaa282] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 12/16/2020] [Accepted: 12/23/2020] [Indexed: 01/03/2023] Open
Abstract
Previously we showed that dimethyl fumarate (DMF) dose-dependently increased mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich's ataxia (FA). Here we tested DMF's ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial copy number in C57BL6 wild-type mice and the FXNKD mouse model of FA. We first dosed DMF at 0-320 mg/kg in C57BL6 mice and observed significant toxicity above 160 mg/kg orally, defining the maximum tolerated dose. Oral dosing of C57BL6 mice in the range 0-160 mg/kg identified a maximum increase in aconitase activity and mitochondrial gene expression in brain and quadriceps at 110 mg/kg DMF, thus defining the maximum effective dose (MED). The MED of DMF in mice overlaps the currently approved human-equivalent doses of DMF prescribed for multiple sclerosis (480 mg/day) and psoriasis (720 mg/day). In the FXNKD mouse model of FA, which has a doxycycline-induced deficit of frataxin protein, we observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4 and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. About 110 mg/kg of oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat FA or other mitochondrial diseases.
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Affiliation(s)
- Chun Kiu Hui
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Elena N Dedkova
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Claire Montgomery
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Gino Cortopassi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
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21
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Stenton SL, Piekutowska-Abramczuk D, Kulterer L, Kopajtich R, Claeys KG, Ciara E, Eisen J, Płoski R, Pronicka E, Malczyk K, Wagner M, Wortmann SB, Prokisch H. Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance. Hum Mutat 2021; 42:310-319. [PMID: 33348459 DOI: 10.1002/humu.24160] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/14/2020] [Accepted: 12/17/2020] [Indexed: 12/20/2022]
Abstract
Ferrodoxin reductase (FDXR) deficiency is a mitochondrial disease described in recent years primarily in association with optic atrophy, acoustic neuropathy, and developmental delays. Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families. These patients show a broad clinical spectrum ranging from Leigh syndrome with early demise and severe infantile-onset encephalopathy, to milder movement disorders. In total nine individual pathogenic variants, of which seven were novel, were identified in FDXR using whole exome sequencing in suspected mitochondrial disease patients. Over 80% of these variants are missense, a challenging variant class in which to determine pathogenic consequence, especially in the setting of nonspecific phenotypes and in the absence of a reliable biomarker, necessitating functional validation. Here we implement an Arh1-null yeast model to confirm the pathogenicity of variants of uncertain significance in FDXR, bypassing the requirement for patient-derived material.
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Affiliation(s)
- Sarah L Stenton
- Institute of Human Genetics, Technische Universität München, Munich, Germany.,Helmholtz Zentrum München, Institute of Neurogenomics, Munich, Germany
| | | | - Lea Kulterer
- Institute of Human Genetics, Technische Universität München, Munich, Germany.,Helmholtz Zentrum München, Institute of Neurogenomics, Munich, Germany
| | - Robert Kopajtich
- Institute of Human Genetics, Technische Universität München, Munich, Germany.,Helmholtz Zentrum München, Institute of Neurogenomics, Munich, Germany
| | - Kristl G Claeys
- Department of Neurology, University Hospitals Leuven, Leuven, Belgium.,Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, KU Leuven, Leuven, Belgium
| | - Elżbieta Ciara
- Department of Medical Genetics, Children's Memorial Health Institute (CMHI) Warsaw, Warsaw, Poland
| | | | - Rafał Płoski
- Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Pronicka
- Department of Medical Genetics, Children's Memorial Health Institute (CMHI) Warsaw, Warsaw, Poland
| | - Katarzyna Malczyk
- Department of Diagnostic Imaging, Children's Memorial Health Institute (CMHI) Warsaw, Warsaw, Poland
| | - Matias Wagner
- Institute of Human Genetics, Technische Universität München, Munich, Germany.,Helmholtz Zentrum München, Institute of Neurogenomics, Munich, Germany
| | - Saskia B Wortmann
- Institute of Human Genetics, Technische Universität München, Munich, Germany.,Helmholtz Zentrum München, Institute of Neurogenomics, Munich, Germany.,Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.,Radboud Centre for Mitochondrial Diseases (RCMM), Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands
| | - Holger Prokisch
- Institute of Human Genetics, Technische Universität München, Munich, Germany.,Helmholtz Zentrum München, Institute of Neurogenomics, Munich, Germany
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Seco-Cervera M, González-Cabo P, Pallardó FV, Romá-Mateo C, García-Giménez JL. Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich's Ataxia. Antioxidants (Basel) 2020; 9:antiox9121257. [PMID: 33321938 PMCID: PMC7763308 DOI: 10.3390/antiox9121257] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/04/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.
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Affiliation(s)
- Marta Seco-Cervera
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
| | - Pilar González-Cabo
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
| | - Federico V. Pallardó
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
| | - Carlos Romá-Mateo
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Correspondence: (C.R.-M.); (J.L.G.-G.); Tel.: +34-963-864-646 (C.R.-M. & J.L.G.-G.)
| | - José Luis García-Giménez
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Correspondence: (C.R.-M.); (J.L.G.-G.); Tel.: +34-963-864-646 (C.R.-M. & J.L.G.-G.)
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23
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Mavrogeni S, Giannakopoulou A, Katsalouli M, Pons RM, Papavasiliou A, Kolovou G, Noutsias M, Papadopoulos G, Karanasios E, Chrousos GP. Friedreich's Ataxia: Case series and the Additive Value of Cardiovascular Magnetic Resonance. J Neuromuscul Dis 2020; 7:61-67. [PMID: 31796683 DOI: 10.3233/jnd-180373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BackgroundFriedreich's ataxia (FA) is an autosomal-recessive neurodegenerative disease characterised by neurologic, cardiac and endocrine abnormalities. Currently, Friedreich cardiomyopathy (FA-CM) staging is based on early ECG findings, high sensitivity troponin (hsTNT) ≥14 ng/ml and echocardiographic left ventricular (LV) morphologic and functional evaluation. However, further parameters, accessible only by cardiovascular magnetic resonance (CMR), such as myocardial oedema, perfusion defects, replacement and/or diffuse myocardial fibrosis, may have a place in the staging of FA-CA. Our aim was to elucidate the additive value of CMR in FA-CM.MethodsThree FA cases were assessed using ECG, 24 h Holter recording, hsTNT, routine ECHO including wall dimension, valvular and ventricular function evaluation and CMR using 1.5T Ingenia system. Ventricular volumes-function, wall dimensions and fibrosis imaging using late gadolinium enhancement (LGE) was performed.ResultsAll FA patients had non-specific ECG changes, almost normal 24 h Holter recording, mild hypertrophy with normal function assessed by echocardiography and increased hsTNT. However, the CMR evaluation revealed the presence of LGE >5% of LV mass, indicative of severe fibrosis. Therefore, the FA patients were re-categorized as having severe FA-CA, although their LVEF remained normal.ConclusionThe combination of classical diagnostic indices and CMR may reveal early asymptomatic FA-CM and motivate the early initiation of cardiac treatment. Furthermore, these indices can be also used to validate specific treatment targets in FA, potentially useful in the prevention of FA-CM.
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Affiliation(s)
| | - Aikaterini Giannakopoulou
- First Department of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - Marina Katsalouli
- First Department of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - Roser Maria Pons
- First Department of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | | | | | - Michel Noutsias
- Mid-German Heart Center, Department of Internal Medicine III (KIM-III), Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle, Ernst-Grube-Strasse 40, D-06120 Halle (Saale), Germany
| | - George Papadopoulos
- First Department of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - Evangelos Karanasios
- First Department of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - George P Chrousos
- First Department of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
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24
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Pérez-Luz S, Loria F, Katsu-Jiménez Y, Oberdoerfer D, Yang OL, Lim F, Muñoz-Blanco JL, Díaz-Nido J. Altered Secretome and ROS Production in Olfactory Mucosa Stem Cells Derived from Friedreich's Ataxia Patients. Int J Mol Sci 2020; 21:ijms21186662. [PMID: 32933002 PMCID: PMC7555998 DOI: 10.3390/ijms21186662] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 09/08/2020] [Indexed: 12/14/2022] Open
Abstract
Friedreich’s ataxia is the most common hereditary ataxia for which there is no cure or approved treatment at present. However, therapeutic developments based on the understanding of pathological mechanisms underlying the disease have advanced considerably, with the implementation of cellular models that mimic the disease playing a crucial role. Human olfactory ecto-mesenchymal stem cells represent a novel model that could prove useful due to their accessibility and neurogenic capacity. Here, we isolated and cultured these stem cells from Friedreich´s ataxia patients and healthy donors, characterizing their phenotype and describing disease-specific features such as reduced cell viability, impaired aconitase activity, increased ROS production and the release of cytokines involved in neuroinflammation. Importantly, we observed a positive effect on patient-derived cells, when frataxin levels were restored, confirming the utility of this in vitro model to study the disease. This model will improve our understanding of Friedreich´s ataxia pathogenesis and will help in developing rationally designed therapeutic strategies.
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Affiliation(s)
- Sara Pérez-Luz
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Departamento de Biología Molecular, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, 28049 Madrid, Spain; (S.P.-L.); (D.O.); (O.-L.Y.); (J.D.-N.)
- Molecular Genetics Unit, Institute of Rare Diseases Research, Institute of Health Carlos III (ISCIII), Ctra. Majadahonda-Pozuelo Km 2,200, 28220 Madrid, Spain
| | - Frida Loria
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Departamento de Biología Molecular, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, 28049 Madrid, Spain; (S.P.-L.); (D.O.); (O.-L.Y.); (J.D.-N.)
- Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Calle Budapest 1, 28922 Madrid, Spain
- Correspondence: ; Tel.: +34-911-964-594
| | - Yurika Katsu-Jiménez
- Karolinska Institutet, Department of Microbiology Tumor and Cell Biology, Solnaväjen 1, 171 77 Stockholm, Sweden;
| | - Daniel Oberdoerfer
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Departamento de Biología Molecular, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, 28049 Madrid, Spain; (S.P.-L.); (D.O.); (O.-L.Y.); (J.D.-N.)
| | - Oscar-Li Yang
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Departamento de Biología Molecular, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, 28049 Madrid, Spain; (S.P.-L.); (D.O.); (O.-L.Y.); (J.D.-N.)
| | - Filip Lim
- Department of Molecular Biology, Autonomous University of Madrid, Francisco Tomás y Valiente 7, 28049 Madrid, Spain;
| | - José Luis Muñoz-Blanco
- Department of Neurology, Hospital Universitario Gregorio Marañón, Dr. Esquerdo 46, 28007 Madrid, Spain;
| | - Javier Díaz-Nido
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Departamento de Biología Molecular, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, 28049 Madrid, Spain; (S.P.-L.); (D.O.); (O.-L.Y.); (J.D.-N.)
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25
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Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion? Antioxidants (Basel) 2020; 9:E664. [PMID: 32722309 PMCID: PMC7465446 DOI: 10.3390/antiox9080664] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/17/2020] [Accepted: 07/19/2020] [Indexed: 12/12/2022] Open
Abstract
Friedreich´s ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those "antioxidant" drugs that went beyond the disease´s models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials.
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Affiliation(s)
- Laura R. Rodríguez
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
| | - Tamara Lapeña
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - Pablo Calap-Quintana
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - María Dolores Moltó
- Department of Genetics, Universitat de València-INCLIVA, 46100 Valencia, Spain;
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 46100 Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
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26
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Maudoux A, Teissier N, Francois M, Van Den Abbeele T, Alberti C, Husson I, Wiener-Vacher SR. Vestibular impact of Friedreich ataxia in early onset patients. CEREBELLUM & ATAXIAS 2020; 7:6. [PMID: 32514364 PMCID: PMC7254732 DOI: 10.1186/s40673-020-00115-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/06/2020] [Indexed: 11/10/2022]
Abstract
Background Friedreich ataxia (FRDA) is the most frequent form of inherited ataxias. Vestibular and auditory assessments are not commonly part of the check up for these patients despite hearing and balance complaints. Screening of vestibular and auditory function was performed in a large group of young patients with genetically confirmed FRDA. Methods Our study included 43 patients (7–24 years of age). A complete vestibular assessment was performed including the canals function evaluation at 3 head velocities (bithermal caloric test, earth vertical axis rotation (EVAR) and head impulse test (HIT)) and otolith function evaluation (cervical vestibular evoked myogenic potentials). Information regarding the hearing evaluation of the patients were also retrieved including impedance tympanometry, distortion product otoacoustic emissions (DPOAEs), air and bone conduction audiometry and auditory brainstem response (ABR). Results Vestibular responses were impaired for canal responses (only at high and middle head velocities) and vestibulospinal otolithic responses. Abnormal neural conduction in the central auditory pathways was frequently observed. Oculomotor abnormalities were frequent, mostly hypermetric saccades and gaze instability. Inhibition of the vestibulo-ocular reflex by fixation was normal. Conclusions We show that Friedreich ataxia, even at onset, frequently associate saccadic intrusions, abnormal ABRs and decreased vestibulo-ocular and vestibulospinal responses progressing over time. These sensory impairments combined with ataxia further impair patient’s autonomy. These vestibular, auditory and visual impairments could be used as markers of the severity and progression of the disease. Adding vestibular and auditory testing to Friedreich patient’s evaluation may help physicians improve patient’s management.
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Affiliation(s)
- A Maudoux
- Center for Balance Evaluation in Children (EFEE), Otolaryngology Department, Assistance Publique des Hôpitaux de Paris, Universitary Robert-Debré Hospital, F-75019 Paris, France.,Université de Paris, U1141, NeuroDiderot, Inserm, F-75019 Paris, France
| | - N Teissier
- Center for Balance Evaluation in Children (EFEE), Otolaryngology Department, Assistance Publique des Hôpitaux de Paris, Universitary Robert-Debré Hospital, F-75019 Paris, France.,Université de Paris, U1141, NeuroDiderot, Inserm, F-75019 Paris, France
| | - M Francois
- Center for Balance Evaluation in Children (EFEE), Otolaryngology Department, Assistance Publique des Hôpitaux de Paris, Universitary Robert-Debré Hospital, F-75019 Paris, France.,Université de Paris, U1141, NeuroDiderot, Inserm, F-75019 Paris, France
| | - Th Van Den Abbeele
- Center for Balance Evaluation in Children (EFEE), Otolaryngology Department, Assistance Publique des Hôpitaux de Paris, Universitary Robert-Debré Hospital, F-75019 Paris, France.,Université de Paris, U1141, NeuroDiderot, Inserm, F-75019 Paris, France
| | - C Alberti
- Clinical Epidemiology unit, Assistance Publique des Hôpitaux de Paris, Robert-Debré Hospital, F-75019 Paris, France.,Unité INSERM CIC-EC 1426, UMR-S 1123, F-75019 Paris, France
| | - I Husson
- Functional Rehabiliation Unit, Assistance Publique des Hôpitaux de Paris, Robert-Debré Hospital, F-75019 Paris, France
| | - S R Wiener-Vacher
- Center for Balance Evaluation in Children (EFEE), Otolaryngology Department, Assistance Publique des Hôpitaux de Paris, Universitary Robert-Debré Hospital, F-75019 Paris, France.,Université de Paris, U1141, NeuroDiderot, Inserm, F-75019 Paris, France
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27
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La Rosa P, Petrillo S, Bertini ES, Piemonte F. Oxidative Stress in DNA Repeat Expansion Disorders: A Focus on NRF2 Signaling Involvement. Biomolecules 2020; 10:biom10050702. [PMID: 32369911 PMCID: PMC7277112 DOI: 10.3390/biom10050702] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
DNA repeat expansion disorders are a group of neuromuscular and neurodegenerative diseases that arise from the inheritance of long tracts of nucleotide repetitions, located in the regulatory region, introns, or inside the coding sequence of a gene. Although loss of protein expression and/or the gain of function of its transcribed mRNA or translated product represent the major pathogenic effect of these pathologies, mitochondrial dysfunction and imbalance in redox homeostasis are reported as common features in these disorders, deeply affecting their severity and progression. In this review, we examine the role that the redox imbalance plays in the pathological mechanisms of DNA expansion disorders and the recent advances on antioxidant treatments, particularly focusing on the expression and the activity of the transcription factor NRF2, the main cellular regulator of the antioxidant response.
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28
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Turchi R, Tortolici F, Guidobaldi G, Iacovelli F, Falconi M, Rufini S, Faraonio R, Casagrande V, Federici M, De Angelis L, Carotti S, Francesconi M, Zingariello M, Morini S, Bernardini R, Mattei M, La Rosa P, Piemonte F, Lettieri-Barbato D, Aquilano K. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue. Cell Death Dis 2020; 11:51. [PMID: 31974344 PMCID: PMC6978516 DOI: 10.1038/s41419-020-2253-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 12/18/2022]
Abstract
Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
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Affiliation(s)
- Riccardo Turchi
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Flavia Tortolici
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Giulio Guidobaldi
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Federico Iacovelli
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Mattia Falconi
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Stefano Rufini
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Raffaella Faraonio
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
| | - Viviana Casagrande
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Lorenzo De Angelis
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Simone Carotti
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Maria Francesconi
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Maria Zingariello
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Sergio Morini
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Roberta Bernardini
- Interdepartmental Service Center-Station for Animal Technology (STA), University of Rome Tor Vergata, Rome, Italy
| | - Maurizio Mattei
- Interdepartmental Service Center-Station for Animal Technology (STA), University of Rome Tor Vergata, Rome, Italy
| | - Piergiorgio La Rosa
- Unit of Neuromuscular and Neurodegenerative Diseases, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Fiorella Piemonte
- Unit of Neuromuscular and Neurodegenerative Diseases, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Daniele Lettieri-Barbato
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy.
- IRCCS Fondazione Santa Lucia, 00143, Rome, Italy.
| | - Katia Aquilano
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy.
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29
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Tatsch E, De Carvalho JAM, Bollick YS, Duarte T, Duarte MMMF, Vaucher RA, Premaor MO, Comim FV, Moresco RN. Low frataxin mRNA expression is associated with inflammation and oxidative stress in patients with type 2 diabetes. Diabetes Metab Res Rev 2020; 36:e3208. [PMID: 31343823 DOI: 10.1002/dmrr.3208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 06/04/2019] [Accepted: 07/16/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND The mitochondrial protein frataxin is involved in iron metabolism, as well as regulation of oxidative stress. To elucidate the association of frataxin with the pathophysiology of diabetes, we evaluated the mRNA levels of frataxin in leukocytes of patients with type 2 diabetes (T2D). In addition, we investigated the relation between frataxin mRNA levels, inflammatory cytokines, and oxidative stress biomarkers. METHODS A study including 150 subjects (115 patients with T2D and 35 healthy subjects) was performed to evaluate the frataxin mRNA levels in leukocytes. We assessed the relation between frataxin and interleukin (IL)-6, IL-1, tumour necrosis factor-alpha (TNF-α), total oxidation status (TOS), total antioxidant capacity (TAC), and serum iron. RESULTS The frataxin mRNA levels in the T2D group were significantly lower than those in healthy subjects. It was also demonstrated that T2D patients with frataxin mRNA levels in the lowest quartile had significantly elevated levels of serum iron, TOS, and inflammatory cytokines, such as TNF-α, IL-1, and IL-6, while TAC levels were significantly lower in this quartile when compared with the upper quartile. CONCLUSIONS Our findings showed that T2D patients with low frataxin mRNA levels showed a high degree of inflammation and oxidative stress. It is speculated that frataxin deficiency in T2D patients can contribute to the imbalance in mitochondrial iron homeostasis leading to the acceleration of oxidative stress and inflammation.
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Affiliation(s)
- Etiane Tatsch
- Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - José A M De Carvalho
- Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, RS, Brazil
- Laboratory of Clinical Analysis, University Hospital, Santa Maria, RS, Brazil
| | - Yãnaí S Bollick
- Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Thiago Duarte
- Laboratory of Biogenomic, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Marta M M F Duarte
- Department of Health Sciences, Lutheran University of Brazil, Santa Maria, RS, Brazil
| | - Rodrigo A Vaucher
- Center of Chemical, Pharmaceutical and Food Sciences, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Melissa O Premaor
- Department of Clinical Medicine, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Fabio V Comim
- Department of Clinical Medicine, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Rafael N Moresco
- Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, RS, Brazil
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30
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Neurochemical profiles in hereditary ataxias: A meta-analysis of Magnetic Resonance Spectroscopy studies. Neurosci Biobehav Rev 2019; 108:854-865. [PMID: 31838195 DOI: 10.1016/j.neubiorev.2019.12.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 12/10/2019] [Accepted: 12/11/2019] [Indexed: 12/12/2022]
Abstract
Magnetic resonance spectroscopy (MRS) is applied to investigate the neurochemical profiles of degenerative hereditary ataxias. This meta-analysis provides a quantitative review and reappraisal of MRS findings in spinocerebellar ataxias (SCA) and Friedreich ataxia (FA) available to date. From each study, changes in N-acetyl aspartate (NAA), choline-containing compounds (Cho) and myo-Inositol (mI) ratios to total creatine (Cr) were calculated for groups of patients (1499 patients in total: SCA1 = 223, SCA2 = 298, SCA3 = 711, SCA6 = 165, and FA = 102) relative to their own control group, mostly in cerebellum and pons. SCA1, 2, 3, 6, and FA patients showed overall decreased NAA/Cr compared to controls. Decreased Cho/Cr was visible in SCA1, 2, and 3 and elevated mI/Cr in SCA2 patients in cerebellum. In SCA6 and FA Cho/Cr and mI/Cr did not differ with respect to controls but SCA6 patients indicated higher Cho/Cr compared to SCA1 patients in cerebellum. SCA2 subjects showed the lowest NAA/Cr and Cho/Cr in cerebellum and the highest mI/Cr compared to controls and other genotypes, and therefore the most promising results for a potential biomarker.
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Garg M, Kulkarni SD, Shah KN, Hegde AU. Diabetes Mellitus as the Presenting Feature of Friedreich's Ataxia. J Neurosci Rural Pract 2019; 8:S117-S119. [PMID: 28936086 PMCID: PMC5602235 DOI: 10.4103/jnrp.jnrp_112_17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Patients with Friedreich's ataxia (FA) are at an increased risk of developing diabetes mellitus and glucose intolerance. Diabetes usually develops many years after the initial presentation. We report an 8-year-old girl who initially presented with diabetic ketoacidosis and was treated as a case of insulin-dependent diabetes mellitus. Around a year later, she developed gait problems and ataxia. Cardiac involvement was detected on echocardiography. Genetic testing confirmed the diagnosis of FA. FA should be a diagnostic consideration in children presenting with diabetes and neurological issues, even with early presentation of the former. Early occurrence of diabetes and rapid progression of ataxia in this patient needs a better understanding of underlying genetic mechanisms.
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Affiliation(s)
- Meenal Garg
- Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Shilpa D Kulkarni
- Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Krishnakumar N Shah
- Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Anaita Udwadia Hegde
- Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
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32
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Geisler JG. 2,4 Dinitrophenol as Medicine. Cells 2019; 8:cells8030280. [PMID: 30909602 PMCID: PMC6468406 DOI: 10.3390/cells8030280] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/11/2019] [Accepted: 03/20/2019] [Indexed: 12/20/2022] Open
Abstract
In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950’s to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and “morning sickness” anti-nausea medication targeting pregnant women in the 1950’s. The “thalidomide babies” became the case-in-point for the need of strict guidelines by the U.S. Food & Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of “social responsibility” allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle’s physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca2+) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca2+ overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer’s Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for “metabesity”, an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP’s induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80’s years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).
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Affiliation(s)
- John G Geisler
- Mitochon Pharmaceuticals, Inc., 970 Cross Lane, Blue Bell, PA 19422, USA.
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Nachun D, Gao F, Isaacs C, Strawser C, Yang Z, Dokuru D, Van Berlo V, Sears R, Farmer J, Perlman S, Lynch DR, Coppola G. Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients. Hum Mol Genet 2019; 27:2965-2977. [PMID: 29790959 PMCID: PMC6097013 DOI: 10.1093/hmg/ddy198] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 05/17/2018] [Indexed: 12/15/2022] Open
Abstract
Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.
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Affiliation(s)
- Daniel Nachun
- Department of Psychiatry and Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA
| | - Fuying Gao
- Department of Psychiatry and Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA
| | - Charles Isaacs
- Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | - Zhongan Yang
- Department of Psychiatry and Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA
| | - Deepika Dokuru
- Department of Psychiatry and Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA
| | - Victoria Van Berlo
- Department of Psychiatry and Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA
| | - Renee Sears
- Department of Psychiatry and Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA
| | | | - Susan Perlman
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA
| | - David R Lynch
- Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Giovanni Coppola
- Department of Psychiatry and Semel Institute, University of California, Los Angeles, Los Angeles, CA, USA.,Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA
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Palandri A, Martin E, Russi M, Rera M, Tricoire H, Monnier V. Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia. Dis Model Mech 2018; 11:dmm033811. [PMID: 29898895 PMCID: PMC6078405 DOI: 10.1242/dmm.033811] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 06/06/2018] [Indexed: 12/30/2022] Open
Abstract
Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, which is characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a Drosophila melanogaster cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions. Here, we used this model to screen in vivo the Prestwick Chemical Library, comprising 1280 compounds. Eleven drugs significantly reduced the cardiac dilatation, some of which may possibly lead to therapeutic applications in the future. The one with the strongest protective effects was paclitaxel, a microtubule-stabilizing drug. In parallel, we characterized the histological defects induced by frataxin deficiency in cardiomyocytes and observed strong sarcomere alterations with loss of striation of actin fibers, along with full disruption of the microtubule network. Paclitaxel and MB both improved these structural defects. Therefore, we propose that frataxin inactivation induces cardiac dysfunction through impaired sarcomere assembly or renewal due to microtubule destabilization, without excluding additional mechanisms. This study is the first drug screening of this extent performed in vivo on a Drosophila model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult Drosophila flies is usable for medium-scale in vivo pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.
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Affiliation(s)
- Amandine Palandri
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Elodie Martin
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Maria Russi
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Michael Rera
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Hervé Tricoire
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Véronique Monnier
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
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Pappa A, Häusler MG, Veigel A, Tzamouranis K, Pfeifer MW, Schmidt A, Bökamp M, Haberland H, Wagner S, Brückel J, de Sousa G, Hackl L, Bollow E, Holl RW. Diabetes mellitus in Friedreich Ataxia: A case series of 19 patients from the German-Austrian diabetes mellitus registry. Diabetes Res Clin Pract 2018; 141:229-236. [PMID: 29763710 DOI: 10.1016/j.diabres.2018.05.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 04/22/2018] [Accepted: 05/08/2018] [Indexed: 10/16/2022]
Abstract
Friedreich ataxia (FRDA) is a multisystem autosomal recessive disease with progressive clinical course involving the neuromuscular and endocrine system. Diabetes mellitus (DM) is one typical non-neurological manifestation, caused by beta cell failure and insulin resistance. Because of its rarity, knowledge on DM in FRDA is limited. Based on data from 200,301 patients with DM of the German-Austrian diabetes registry (DPV) and two exemplary patient reports, characteristics of patients with DM and FRDA are compared with classical type 1 or type 2 diabetes. Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ± 165 and 384 ± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups. FRDA patients did not show overweight and HbA1c levels were even lower than in T1Dm or T2Dm patients, respectively, indicating good overall diabetes control. FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.
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Affiliation(s)
- Angeliki Pappa
- Dept. of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany.
| | - Martin G Häusler
- Dept. of Pediatrics, Division of Neuropediatrics and Social Pediatrics, University Hospital RWTH Aachen, Germany
| | - Andreas Veigel
- Childrens Hospital Städtisches Klinikum Karlsruhe, Germany
| | | | | | - Andreas Schmidt
- Diabeteszentrum Dept. of Pediatrics, Christophorus-Kliniken Coesfeld, Germany
| | - Martin Bökamp
- Dpt. of Internal Medicine, Christophorus Kliniken Coesfeld/Duelmen, Germany
| | - Holger Haberland
- DiabetesZentrum für Kinder und Jugendliche Sana Kliniken Berlin-Brandenburg, Germany
| | | | | | | | - Lukas Hackl
- Dept. of Pediatrics, Medical University Innsbruck, Austria
| | - Esther Bollow
- Institute for Epidemiology and medical Biometry, ZIBMT, University of Ulm, Germany; German Center for Diabetes-Research (DZD), Munich-Neuherberg, Germany
| | - Reinhard W Holl
- Institute for Epidemiology and medical Biometry, ZIBMT, University of Ulm, Germany; German Center for Diabetes-Research (DZD), Munich-Neuherberg, Germany
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Fex M, Nicholas LM, Vishnu N, Medina A, Sharoyko VV, Nicholls DG, Spégel P, Mulder H. The pathogenetic role of β-cell mitochondria in type 2 diabetes. J Endocrinol 2018; 236:R145-R159. [PMID: 29431147 DOI: 10.1530/joe-17-0367] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/15/2018] [Indexed: 12/17/2022]
Abstract
Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.
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Affiliation(s)
- Malin Fex
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Lisa M Nicholas
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Neelanjan Vishnu
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Anya Medina
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Vladimir V Sharoyko
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - David G Nicholls
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Peter Spégel
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
- Department of ChemistryCenter for Analysis and Synthesis, Lund University, Sweden
| | - Hindrik Mulder
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
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Han L, Maciejewski M, Brockel C, Afzelius L, Altman RB. Mendelian Disease Associations Reveal Novel Insights into Inflammatory Bowel Disease. Inflamm Bowel Dis 2018; 24:471-481. [PMID: 29462399 PMCID: PMC6037048 DOI: 10.1093/ibd/izx087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Indexed: 12/14/2022]
Abstract
Background Monogenic diseases have been shown to contribute to complex disease risk and may hold new insights into the underlying biological mechanism of Inflammatory Bowel Disease (IBD). Methods We analyzed Mendelian disease associations with IBD using over 55 million patients from the Optum's deidentified electronic health records dataset database. Using the significant Mendelian diseases, we performed pathway enrichment analysis and constructed a model using gene expression datasets to differentiate Crohn's disease (CD), ulcerative colitis (UC), and healthy patient samples. Results We found 50 Mendelian diseases were significantly associated with IBD, with 40 being significantly associated with both CD and UC. Our results for CD replicated those from previous studies. Pathways that were enriched consisted of mainly immune and metabolic processes with a focus on tolerance and oxidative stress. Our 3-way classifier for UC, CD, and healthy samples yielded an accuracy of 72%. Conclusions Mendelian diseases that are significantly associated with IBD may reveal novel insights into the genetic architecture of IBD.
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Affiliation(s)
- Lichy Han
- Biomedical Informatics Training Program, Stanford University, Stanford, CA
| | | | | | | | - Russ B Altman
- Biomedical Informatics Training Program, Stanford University, Stanford, CA
- Department of Genetics, Stanford University, Stanford, CA
- Department of Bioengineering, Stanford University, Stanford, CA
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38
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Affiliation(s)
| | - Sylvia Bösch
- Neurology Department, Innsbruck Medical University, Innsbruck, Austria
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39
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Byard RW, Gilbert JD. Mechanisms of unexpected death and autopsy findings in Friedreich ataxia. MEDICINE, SCIENCE, AND THE LAW 2017; 57:192-196. [PMID: 28803513 DOI: 10.1177/0025802417723809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
A 36-year-old woman with a clinical history of Friedreich ataxia and hypertrophic cardiomyopathy was found unexpectedly dead at her home. The heart showed asymmetric left ventricular hypertrophy, with an interventricular septal thickness of 20-25 mm (the remainder of the left ventricular wall measured 15 mm). Histologically, both ventricles had irregular areas of marked myocyte hypertrophy with associated interstitial fibrosis and focal myofibre disarray. There was neuronal loss within the dentate nucleus of the cerebellum, with vacuolation and axonal loss in the dorsal columns and spinocerebellar tracts of the upper cervical spinal cord. Death was due to hypertrophic cardiomyopathy complicating Friedreich ataxia. Other causes of death in this condition include embolic stroke, cerebral haemorrhage, aspiration pneumonia, renal failure, diabetic ketoacidosis, myocardial infarction, generalised inanition and trauma. Sudden death due to cardiac disease, resulting in presentation for medicolegal autopsy, may be the presenting feature at all ages, including childhood.
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Affiliation(s)
- Roger W Byard
- 1 The University of Adelaide Medical School, Australia
- 2 Forensic Science SA, Australia
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McCormick A, Farmer J, Perlman S, Delatycki M, Wilmot G, Matthews K, Yoon G, Hoyle C, Subramony SH, Zesiewicz T, Lynch DR, McCormack SE. Impact of diabetes in the Friedreich ataxia clinical outcome measures study. Ann Clin Transl Neurol 2017; 4:622-631. [PMID: 28904984 PMCID: PMC5590524 DOI: 10.1002/acn3.439] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 06/12/2017] [Accepted: 06/19/2017] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Friedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age-specific prevalence of FA-associated DM and its impact on neurologic outcomes. RESEARCH DESIGN AND METHODS Participants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes. RESULTS Mean age of participants was 30.1 years (SD 15.3, range: 7-82), 50% were female, and 94% were non-Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA-associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: -0.56-0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals. CONCLUSIONS DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function.
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Affiliation(s)
- Ashley McCormick
- Division of NeurologyChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvania19104
| | - Jennifer Farmer
- Division of NeurologyChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvania19104
- Department of NeurologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
- Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
| | - Susan Perlman
- Department of NeurologyUniversity of California Los AngelesLos AngelesCalifornia90095
| | - Martin Delatycki
- Department of GeneticsMurdoch Children's Research InstituteVictoriaAustralia
| | - George Wilmot
- Department of NeurologyEmory University School of MedicineAtlantaGeorgia30322
| | - Katherine Matthews
- Department of NeurologyUniversity of Iowa Carver College of MedicineIowa CityIowa52242
| | - Grace Yoon
- Clinical and Metabolic GeneticsHospital for Sick ChildrenTorontoCanada
| | - Chad Hoyle
- Department of NeurologyOhio State University College of MedicineColumbusOhio43210
| | - Sub H. Subramony
- Department of NeurologyUniversity of FloridaCollege of MedicineGainesvilleFlorida32610
| | | | - David R. Lynch
- Division of NeurologyChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvania19104
- Department of NeurologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
- Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
| | - Shana E. McCormack
- Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
- Division of Endocrinology and DiabetesChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvania19104
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Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich's ataxia patients. Sci Rep 2017; 7:5237. [PMID: 28701783 PMCID: PMC5507909 DOI: 10.1038/s41598-017-04996-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 05/23/2017] [Indexed: 11/12/2022] Open
Abstract
MicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich’s ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich’s ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated. We found seven differentially expressed miRNAs, and we propose that these miRNAs represent key mechanisms in the modulation of several signalling pathways that regulate the physiopathology of FRDA. If this is the case, miRNAs can be used to characterize phenotypic variation in FRDA and stratify patients’ risk of cardiomyopathy. In this study, we identify miR-323-3p as a candidate marker for phenotypic differentiation in FRDA patients suffering from cardiomyopathy. We propose the use of dynamic miRNAs as biomarkers for phenotypic characterization and prognosis of FRDA.
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Bürk K. Friedreich Ataxia: current status and future prospects. CEREBELLUM & ATAXIAS 2017; 4:4. [PMID: 28405347 PMCID: PMC5383992 DOI: 10.1186/s40673-017-0062-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 03/24/2017] [Indexed: 01/23/2023]
Abstract
Friedreich ataxia (FA) represents the most frequent type of inherited ataxia. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Due to epigenetic alterations, frataxin expression is significantly reduced. Frataxin is a mitochondrial protein. Its deficiency leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species. This review gives an overview over clinical and genetic aspects of FA and discusses current concepts of frataxin biogenesis and function as well as new therapeutic strategies.
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Affiliation(s)
- Katrin Bürk
- University of Marburg, and Paracelsus-Elena Klinik, Klinikstr. 16, 34128 Kassel, Germany
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Gerber PA, Rutter GA. The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus. Antioxid Redox Signal 2017; 26:501-518. [PMID: 27225690 PMCID: PMC5372767 DOI: 10.1089/ars.2016.6755] [Citation(s) in RCA: 438] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 05/25/2016] [Indexed: 12/16/2022]
Abstract
SIGNIFICANCE Metabolic syndrome is a frequent precursor of type 2 diabetes mellitus (T2D), a disease that currently affects ∼8% of the adult population worldwide. Pancreatic beta-cell dysfunction and loss are central to the disease process, although understanding of the underlying molecular mechanisms is still fragmentary. Recent Advances: Oversupply of nutrients, including glucose and fatty acids, and the subsequent overstimulation of beta cells, are believed to be an important contributor to insulin secretory failure in T2D. Hypoxia has also recently been implicated in beta-cell damage. Accumulating evidence points to a role for oxidative stress in both processes. Although the production of reactive oxygen species (ROS) results from enhanced mitochondrial respiration during stimulation with glucose and other fuels, the expression of antioxidant defense genes is unusually low (or disallowed) in beta cells. CRITICAL ISSUES Not all subjects with metabolic syndrome and hyperglycemia go on to develop full-blown diabetes, implying an important role in disease risk for gene-environment interactions. Possession of common risk alleles at the SLC30A8 locus, encoding the beta-cell granule zinc transporter ZnT8, may affect cytosolic Zn2+ concentrations and thus susceptibility to hypoxia and oxidative stress. FUTURE DIRECTIONS Loss of normal beta-cell function, rather than total mass, is increasingly considered to be the major driver for impaired insulin secretion in diabetes. Better understanding of the role of oxidative changes, its modulation by genes involved in disease risk, and effects on beta-cell identity may facilitate the development of new therapeutic strategies to this disease. Antioxid. Redox Signal. 26, 501-518.
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Affiliation(s)
- Philipp A. Gerber
- Department of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, United Kingdom
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Benini M, Fortuni S, Condò I, Alfedi G, Malisan F, Toschi N, Serio D, Massaro DS, Arcuri G, Testi R, Rufini A. E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia. Cell Rep 2017; 18:2007-2017. [PMID: 28228265 PMCID: PMC5329121 DOI: 10.1016/j.celrep.2017.01.079] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 12/14/2016] [Accepted: 01/29/2017] [Indexed: 12/21/2022] Open
Abstract
Friedreich ataxia (FRDA) is a severe genetic neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. To date, there is no therapy to treat this condition. The amount of residual frataxin critically affects the severity of the disease; thus, attempts to restore physiological frataxin levels are considered therapeutically relevant. Frataxin levels are controlled by the ubiquitin-proteasome system; therefore, inhibition of the frataxin E3 ligase may represent a strategy to achieve an increase in frataxin levels. Here, we report the identification of the RING E3 ligase RNF126 as the enzyme that specifically mediates frataxin ubiquitination and targets it for degradation. RNF126 interacts with frataxin and promotes its ubiquitination in a catalytic activity-dependent manner, both in vivo and in vitro. Most importantly, RNF126 depletion results in frataxin accumulation in cells derived from FRDA patients, highlighting the relevance of RNF126 as a new therapeutic target for Friedreich ataxia.
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Affiliation(s)
- Monica Benini
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Fratagene Therapeutics Srl, Viale dei Campioni 8, 00144 Rome, Italy
| | - Silvia Fortuni
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy
| | - Ivano Condò
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy
| | - Giulia Alfedi
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy
| | - Florence Malisan
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy
| | - Nicola Toschi
- Medical Physics Section, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging and Harvard Medical School, Boston, MA 02115, USA
| | - Dario Serio
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Fratagene Therapeutics Srl, Viale dei Campioni 8, 00144 Rome, Italy
| | - Damiano Sergio Massaro
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy
| | - Gaetano Arcuri
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy
| | - Roberto Testi
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Fratagene Therapeutics Srl, Viale dei Campioni 8, 00144 Rome, Italy
| | - Alessandra Rufini
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Fratagene Therapeutics Srl, Viale dei Campioni 8, 00144 Rome, Italy.
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López Del Amo V, Palomino-Schätzlein M, Seco-Cervera M, García-Giménez JL, Pallardó FV, Pineda-Lucena A, Galindo MI. A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration. Biochim Biophys Acta Mol Basis Dis 2017; 1863:801-809. [PMID: 28065847 DOI: 10.1016/j.bbadis.2017.01.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 12/13/2016] [Accepted: 01/04/2017] [Indexed: 01/07/2023]
Abstract
Charcot-Marie-Tooth disease is a rare peripheral neuropathy for which there is no specific treatment. Some forms of Charcot-Marie-Tooth are due to mutations in the GDAP1 gene. A striking feature of mutations in GDAP1 is that they have a variable clinical manifestation, according to disease onset and progression, histology and mode of inheritance. Studies in cellular and animal models have revealed a role of GDAP1 in mitochondrial morphology and distribution, calcium homeostasis and oxidative stress. To get a better understanding of the disease mechanism we have generated models of over-expression and RNA interference of the Drosophila Gdap1 gene. In order to get an overview about the changes that Gdap1 mutations cause in our disease model, we have combined a comprehensive determination of the metabolic profile in the flies by nuclear magnetic resonance spectroscopy with gene expression analyses and biophysical tests. Our results revealed that both up- and down-regulation of Gdap1 results in an early systemic inactivation of the insulin pathway before the onset of neuromuscular degeneration, followed by an accumulation of carbohydrates and an increase in the β-oxidation of lipids. Our findings are in line with emerging reports of energy metabolism impairments linked to different types of neural pathologies caused by defective mitochondrial function, which is not surprising given the central role of mitochondria in the control of energy metabolism. The relationship of mitochondrial dynamics with metabolism during neurodegeneration opens new avenues to understand the cause of the disease, and for the discovery of new biomarkers and treatments.
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Affiliation(s)
- Víctor López Del Amo
- Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), 46012 Valencia, Spain
| | | | - Marta Seco-Cervera
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 46012 Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
| | - José Luis García-Giménez
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 46012 Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
| | - Federico Vicente Pallardó
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 46012 Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
| | - Antonio Pineda-Lucena
- Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; Drug Discovery Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Máximo Ibo Galindo
- Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; IDM-Institute of Molecular Recognition, Universidad Politécnica de Valencia, 46022 Valencia, Spain; UPV-CIPF Joint Unit Disease Mechanisms and Nanomedicine, Valencia, Spain.
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46
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Codazzi F, Hu A, Rai M, Donatello S, Salerno Scarzella F, Mangiameli E, Pelizzoni I, Grohovaz F, Pandolfo M. Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor. Hum Mol Genet 2016; 25:4847-4855. [PMID: 28175303 DOI: 10.1093/hmg/ddw308] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 08/07/2016] [Accepted: 08/26/2016] [Indexed: 01/08/2023] Open
Abstract
We employed induced pluripotent stem cell (iPSC)-derived neurons obtained from Friedreich ataxia (FRDA) patients and healthy subjects, FRDA neurons and CT neurons, respectively, to unveil phenotypic alterations related to frataxin (FXN) deficiency and investigate if they can be reversed by treatments that upregulate FXN. FRDA and control iPSCs were equally capable of differentiating into a neuronal or astrocytic phenotype. FRDA neurons showed lower levels of iron–sulfur (Fe–S) and lipoic acid-containing proteins, higher labile iron pool (LIP), higher expression of mitochondrial superoxide dismutase (SOD2), increased reactive oxygen species (ROS) and lower reduced glutathione (GSH) levels, and enhanced sensitivity to oxidants compared with CT neurons, indicating deficient Fe–S cluster biogenesis, altered iron metabolism, and oxidative stress. Treatment with the benzamide HDAC inhibitor 109 significantly upregulated FXN expression and increased Fe–S and lipoic acid-containing protein levels, downregulated SOD2 levels, normalized LIP and ROS levels, and almost fully protected FRDA neurons from oxidative stress-mediated cell death. Our findings suggest that correction of FXN deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.
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Affiliation(s)
- Franca Codazzi
- IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Amelié Hu
- Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Myriam Rai
- Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Simona Donatello
- Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | | | | | | | - Fabio Grohovaz
- IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Massimo Pandolfo
- Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Tamarit J, Obis È, Ros J. Oxidative stress and altered lipid metabolism in Friedreich ataxia. Free Radic Biol Med 2016; 100:138-146. [PMID: 27296838 DOI: 10.1016/j.freeradbiomed.2016.06.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 06/07/2016] [Accepted: 06/10/2016] [Indexed: 12/31/2022]
Abstract
Friedreich ataxia is a genetic disease caused by the deficiency of frataxin, a mitochondrial protein. Frataxin deficiency impacts in the cell physiology at several levels. One of them is oxidative stress with consequences in terms of protein dysfunctions and metabolic alterations. Among others, alterations in lipid metabolism have been observed in several models of the disease. In this review we summarize the current knowledge of the molecular basis of the disease, the relevance of oxidative stress and the therapeutic strategies based on reduction of mitochondrial reactive oxygen species production. Finally, we will focus the interest in alterations of lipid metabolism as a consequence of mitochondrial dysfunction and describe the therapeutic approaches based on targeting lipid metabolism.
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Affiliation(s)
- Jordi Tamarit
- Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, Lleida, Spain
| | - Èlia Obis
- Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, Lleida, Spain
| | - Joaquim Ros
- Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, Lleida, Spain.
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48
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Galea CA, Huq A, Lockhart PJ, Tai G, Corben LA, Yiu EM, Gurrin LC, Lynch DR, Gelbard S, Durr A, Pousset F, Parkinson M, Labrum R, Giunti P, Perlman SL, Delatycki MB, Evans-Galea MV. Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia. Ann Neurol 2016; 79:485-95. [PMID: 26704351 DOI: 10.1002/ana.24595] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/16/2015] [Accepted: 12/17/2015] [Indexed: 02/01/2023]
Abstract
OBJECTIVE Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur in 96% of affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA. METHODS We compared clinical information from 111 compound heterozygotes and 131 individuals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (1) homozygous expansions, and three compound heterozygote groups; (2) null (no frataxin produced); (3) moderate/strong impact; and (4) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses. RESULTS Mutations in the hydrophobic core of frataxin affected stability whereas surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus, compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups. INTERPRETATION In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provide a definitive resource for investigating disease pathogenesis in FRDA.
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Affiliation(s)
- Charles A Galea
- Medicinal Chemistry and Drug Delivery, Disposition and Dynamics (D4), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
| | - Aamira Huq
- Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
| | - Paul J Lockhart
- Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Geneieve Tai
- Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
| | - Louise A Corben
- Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
- School of Psychological Sciences, Monash University, Clayton, Victoria, Australia
| | - Eppie M Yiu
- Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
- Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Lyle C Gurrin
- Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - David R Lynch
- Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA
| | - Sarah Gelbard
- Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA
| | - Alexandra Durr
- APHP, Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
- Institut du Cerveau et de la Moelle épinière (ICM), Pitié-Salpêtrière University Hospital, Paris, France
- Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S_1127, ICM, F-75013, France
| | - Francoise Pousset
- APHP, Cardiology Department, AP-HP Pitie-Salpétrière Hospital, Paris, France
| | - Michael Parkinson
- Department of Molecular Neuroscience, University College London Institute of Neurology, London, United Kingdom
| | - Robyn Labrum
- Department of Neurogenetics, University College London Hospital, Institute of Neurology, London, United Kingdom
| | - Paola Giunti
- Department of Molecular Neuroscience, University College London Institute of Neurology, London, United Kingdom
- Department of Neurogenetics, University College London Hospital, Institute of Neurology, London, United Kingdom
| | - Susan L Perlman
- Ataxia Center and Huntington Disease Center of Excellence, Department of Neurology, David Geffen School of Medicine at the University of California at Los Angeles, CA
| | - Martin B Delatycki
- Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
- School of Psychological Sciences, Monash University, Clayton, Victoria, Australia
- Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
| | - Marguerite V Evans-Galea
- Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
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Turkmenoglu FP, Kasirga UB, Celik HH. Ultra-structural hair alterations in Friedreich's ataxia: A scanning electron microscopic investigation. Microsc Res Tech 2015; 78:731-6. [PMID: 26138268 DOI: 10.1002/jemt.22531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 05/05/2015] [Accepted: 05/22/2015] [Indexed: 11/07/2022]
Abstract
Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder involving progressive damage to the central and peripheral nervous systems and cardiomyopathy. FRDA is caused by the silencing of the FXN gene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. Skin disorders including hair abnormalities have previously been reported in patients with mitochondrial disorders. However, to our knowledge, ultra-structural hair alterations in FRDA were not demonstrated. The purpose of this study was to determine ultra-structural alterations in the hairs of FRDA patients as well as carriers. Hair specimen from four patients, who are in different stages of the disease, and two carriers were examined by scanning electron microscope. Thin and weak hair follicles with absence of homogeneities on the cuticular surface, local damages of the cuticular layer, cuticular fractures were detected in both carriers and patients, but these alterations were much more prominent in the hair follicles of patients. In addition, erosions on the surface of the cuticle and local deep cavities just under the cuticular level were observed only in patients. Indistinct cuticular pattern, pores on the cuticular surface, and presence of concavities on the hair follicle were also detected in patients in later stages of the disease. According to our results, progression of the disease increased the alterations on hair structure. We suggest that ultra-structural alterations observed in hair samples might be due to oxidative stress caused by deficient frataxin expression in mitochondria.
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Affiliation(s)
- F Pinar Turkmenoglu
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - U Baran Kasirga
- Department of Anatomy, Faculty of Medicine, Maltepe University, Ankara, Turkey
| | - H Hamdi Celik
- Department of Anatomy, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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50
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Weidemann F, Liu D, Hu K, Florescu C, Niemann M, Herrmann S, Kramer B, Klebe S, Doppler K, Üçeyler N, Ritter CO, Ertl G, Störk S. The cardiomyopathy in Friedreich's ataxia - New biomarker for staging cardiac involvement. Int J Cardiol 2015; 194:50-7. [PMID: 26005806 DOI: 10.1016/j.ijcard.2015.05.074] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 05/08/2015] [Accepted: 05/14/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Patients with autosomal-recessively inherited Friedreich's ataxia (FA) may develop a hypertrophic cardiomyopathy (CM), which potentially progresses towards a life-limiting problem. The typical features of this CM and the sequence of progression are widely unknown. METHODS Thirty-two consecutive patients with genetically confirmed FA were included. All patients received resting electrocardiogram (ECG), 24-hour Holter-ECG, echocardiography with speckle tracking imaging, cardiac magnetic resonance imaging (cMRI) with late enhancement imaging (for replacement fibrosis), and measurement of high-sensitive troponin-T (hsTNT). In addition, morphological parameters were retrospectively compared to data obtained five years before. RESULTS Based on criteria comprising ejection fraction (<55%), left ventricular end-diastolic posterior wall thickness (LVPWT ≥ 11 mm), fibrosis on cMRI, hsTNT ≥ 14 ng/ml, or T-wave-inversion, in all but two patients a CM could be detected (94%). Using these criteria we propose the following staging: a) mild CM (n=5, 16%; T-wave-inversion only); b) intermediate CM (n=4, 13%; T-wave-inversion with hypertrophy but no fibrosis); c) severe CM (n=13, 41%; fibrosis with raised hsTNT); and d) end-stage CM (n=8; 25%; ejection-fraction<55%). All patients with end-stage CM also showed fibrosis on cMRI, T-wave-inversion, marked elevation in hsTNT, and a decrease in LVPWT during the last five years (from 10.7 ± 1.2mm to 9.5 ± 1.3mm, p=0.025). In addition, 38% suffered from supraventricular tachycardia on Holter-ECG. CONCLUSIONS A comprehensive cardiac assessment will unravel established CM in almost all patients with FA with electrocardiographic abnormalities as earliest signs. Advanced stages can be characterized by elevated hsTNT and replacement fibrosis leading to recession of hypertrophy, reduction of global myocardial function, and electrical instability.
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Affiliation(s)
- Frank Weidemann
- Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany; Medical Clinic II, Katharinen-Hospital, Unna, Germany.
| | - Dan Liu
- Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Kai Hu
- Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Cristiane Florescu
- Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Markus Niemann
- Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Sebastian Herrmann
- Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Bastian Kramer
- Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Stephan Klebe
- Department of Neurology, University of Würzburg, Würzburg, Germany
| | - Kathrin Doppler
- Department of Neurology, University of Würzburg, Würzburg, Germany
| | - Nurcan Üçeyler
- Department of Neurology, University of Würzburg, Würzburg, Germany
| | | | - Georg Ertl
- Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Stefan Störk
- Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
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