|
1
|
Lynch DR, Subramony S, Lin KY, Mathews K, Perlman S, Yoon G, Rummey C. Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia. Pediatr Cardiol 2025; 46:379-382. [PMID: 38427090 DOI: 10.1007/s00246-024-03429-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 01/23/2024] [Indexed: 03/02/2024]
Abstract
We examined the clinical features of Friedreich ataxia (FRDA) patients who present first with cardiac disease in order to understand the earliest features of the diagnostic journey in FRDA. We identified a group of subjects in the FACOMS natural history study whose first identified clinical feature was cardiac. Only 0.5% of the total cohort belonged to this group, which was younger on average at the time of presentation. Their cardiac symptoms ranged from asymptomatic features to heart failure with severe systolic dysfunction. Two of those individuals with severe dysfunction proceeded to heart transplantation, but others spontaneously recovered. In most cases, diagnosis of FRDA was not made until well after cardiac presentation. The present study shows that some FRDA patients present based on cardiac features, suggesting that earlier identification of FRDA might occur through enhancing awareness of FRDA among pediatric cardiologists who see such patients. This is important in the context of newly identified therapies for FRDA.
Collapse
Affiliation(s)
- David R Lynch
- Penn/CHOP Friedreich Ataxia Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Departments of Pediatrics and Neurology, Perelman School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 502F Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA, 19104-4318, Switzerland.
| | - Sub Subramony
- Department of Neurology, University of Florida, Gainesville, FL, 32608, USA
| | - Kimberly Y Lin
- Penn/CHOP Friedreich Ataxia Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Cardiology, Department of Pediatrics, Perelman School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Katherine Mathews
- Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Susan Perlman
- Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Grace Yoon
- Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | | |
Collapse
|
|
2
|
Salinas L, Montgomery CB, Figueroa F, Thai PN, Chiamvimonvat N, Cortopassi G, Dedkova EN. Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy. Commun Biol 2024; 7:1250. [PMID: 39363102 PMCID: PMC11449905 DOI: 10.1038/s42003-024-06962-4] [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: 04/17/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024] Open
Abstract
Friedreich's ataxia (FA) is an autosomal recessive disorder caused by reduced frataxin (FXN) expression in mitochondria, where the lethal component is cardiomyopathy. Using the conditional Fxnflox/null::MCK-Cre knock-out (Fxn-cKO) mouse model, we discovered significant sex differences in the progression towards heart failure, with Fxn-cKO males exhibiting a worse cardiac phenotype, low survival rate, kidney and reproductive organ deficiencies. These differences are likely due to a decline in testosterone in Fxn-cKO males. The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.
Collapse
Grants
- T32 HL086350 NHLBI NIH HHS
- R01 HL085727 NHLBI NIH HHS
- I01 CX001490 CSRD VA
- R01 HL101235 NHLBI NIH HHS
- R01 HL137228 NHLBI NIH HHS
- I01 BX000576 BLRD VA
- S10 OD010389 NIH HHS
- R01 HL085844 NHLBI NIH HHS
- R01 HL155907 NHLBI NIH HHS
- 1R01HL155907-1 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- F32 HL149288 NHLBI NIH HHS
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- Friedreich's Ataxia Research Alliance (FARA)
- University of California Davis CRCF Pilot & Feasibility Award 181031 (to END), University of California Innovative Development Award (to END) Harold S. Geneen Charitable Trust Awards Program for Coronary Heart Disease Research (to PNT) VA Merit Review Grant I01 BX000576 and I01 CX001490 (to NC) Research Award from the Rosenfeld Foundation (to NC.
- Pre-doctoral fellowship from NIH R01HL155907-02S1 Diversity Supplement (to LS).
- Pre-doctoral fellowship from NIH T32 HL086350 Training Grant in Basic & Translational Cardiovascular Science
- Postdoctoral fellowship from NIH T32HL086350 Training Grant in Basic & Translational Cardiovascular Science and NIH F32HL149288 and Harold S. Geneen Charitable Trust Awards Program for Coronary Heart Disease Research (to PNT).
- NIH R01 HL085727, HL085844, HL137228, VA Merit Review Grant I01 BX000576 and I01 CX001490, AHA 23SFRNCCS1052478, 23SFRNPCS1060482, and Research Award from the Rosenfeld Foundation (to NC).
Collapse
Affiliation(s)
- Lili Salinas
- Department of Molecular Biosciences, University of California, Davis, CA, USA
| | - Claire B Montgomery
- Department of Molecular Biosciences, University of California, Davis, CA, USA
| | - Francisco Figueroa
- Department of Molecular Biosciences, University of California, Davis, CA, USA
| | - Phung N Thai
- Department of Internal Medicine, University of California, Davis, CA, USA
- Department of Veterans Affairs, Northern California Health Care System, Mather, CA, USA
| | - Nipavan Chiamvimonvat
- Department of Internal Medicine, University of California, Davis, CA, USA
- Department of Veterans Affairs, Northern California Health Care System, Mather, CA, USA
| | - Gino Cortopassi
- Department of Molecular Biosciences, University of California, Davis, CA, USA
| | - Elena N Dedkova
- Department of Molecular Biosciences, University of California, Davis, CA, USA.
- Department of Basic Sciences, California Northstate University, Elk Grove, CA, USA.
| |
Collapse
|
|
3
|
Mosbach V, Puccio H. A multiple animal and cellular models approach to study frataxin deficiency in Friedreich Ataxia. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119809. [PMID: 39134123 DOI: 10.1016/j.bbamcr.2024.119809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 08/01/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024]
Abstract
Friedreich's ataxia (FA) is one of the most frequent inherited recessive ataxias characterized by a progressive sensory and spinocerebellar ataxia. The main causative mutation is a GAA repeat expansion in the first intron of the frataxin (FXN) gene which leads to a transcriptional silencing of the gene resulting in a deficit in FXN protein. The nature of the mutation (an unstable GAA expansion), as well as the multi-systemic nature of the disease (with neural and non-neural sites affected) make the generation of models for Friedreich's ataxia quite challenging. Over the years, several cellular and animal models for FA have been developed. These models are all complementary and possess their own strengths to investigate different aspects of the disease, such as the epigenetics of the locus or the pathophysiology of the disease, as well as being used to developed novel therapeutic approaches. This review will explore the recent advancements in the different mammalian models developed for FA.
Collapse
Affiliation(s)
- Valentine Mosbach
- Institut NeuroMyoGene-PGNM UCBL-CNRS UMR5261 INSERM U1315, Lyon, France
| | - Hélène Puccio
- Institut NeuroMyoGene-PGNM UCBL-CNRS UMR5261 INSERM U1315, Lyon, France.
| |
Collapse
|
|
4
|
Lynch DR, Sharma S, Hearle P, Greeley N, Gunther K, Keita M, Strawser C, Hauser L, Park C, Schadt K, Lin KY. Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia. J Neurol Sci 2024; 461:123053. [PMID: 38759249 DOI: 10.1016/j.jns.2024.123053] [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: 02/13/2024] [Revised: 04/18/2024] [Accepted: 05/13/2024] [Indexed: 05/19/2024]
Abstract
Friedreich ataxia is a progressive autosomal recessive neurodegenerative disorder characterized by ataxia, dyscoordination, and cardiomyopathy. A subset of patients with Friedreich ataxia have elevated levels of serum cardiac troponin I, but associations with disease outcomes and features of cardiomyopathy remain unclear. In this study, we characterized clinically obtained serum cardiac biomarker levels including troponin I, troponin T, and B-type natriuretic peptide in subjects with Friedreich ataxia and evaluated their association with markers of disease. While unprovoked troponin I levels were elevated in 36% of the cohort, cTnI levels associated with a cardiac event (provoked) were higher than unprovoked levels. In multivariate linear regression models, younger age predicted increased troponin I values, and in logistic regression models younger age, female sex, and marginally longer GAA repeat length predicted abnormal troponin I levels. In subjects with multiple assessments, mean unprovoked troponin I levels decreased slightly over time. The presence of abnormal troponin I values and their levels were predicted by echocardiographic measures of hypertrophy. In addition, troponin I levels predicted long-term markers of clinical cardiac dysfunction over time to a modest degree. Consequently, troponin I values provide a marker of hypertrophy but only a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia.
Collapse
Affiliation(s)
- David R Lynch
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America.
| | - Sonal Sharma
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Patrick Hearle
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Nathaniel Greeley
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Katherine Gunther
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Medina Keita
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Cassandra Strawser
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Lauren Hauser
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Courtney Park
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Kimberly Schadt
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Kimberly Y Lin
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America; Divisions of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| |
Collapse
|
|
5
|
Chang JC, Ryan MR, Stark MC, Liu S, Purushothaman P, Bolan F, Johnson CA, Champe M, Meng H, Lawlor MW, Halawani S, Ngaba LV, Lynch DR, Davis C, Gonzalo-Gil E, Lutz C, Urbinati F, Medicherla B, Fonck C. AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich's ataxia. Mol Ther Methods Clin Dev 2024; 32:101193. [PMID: 38352270 PMCID: PMC10862410 DOI: 10.1016/j.omtm.2024.101193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 01/18/2024] [Indexed: 02/16/2024]
Abstract
Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has an FXN gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.
Collapse
Affiliation(s)
- Joshua C. Chang
- Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| | - Molly R. Ryan
- Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| | - Marie C. Stark
- Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| | - Su Liu
- Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| | | | - Fria Bolan
- Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| | | | - Mark Champe
- Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| | - Hui Meng
- Diverge Translational Science Laboratory, Milwaukee, WI 53204, USA
- Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI 53226, USA
| | - Michael W. Lawlor
- Diverge Translational Science Laboratory, Milwaukee, WI 53204, USA
- Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI 53226, USA
| | - Sarah Halawani
- Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Lucie V. Ngaba
- Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - David R. Lynch
- Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | | | | | | | - Fabrizia Urbinati
- Formerly of Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| | - Bala Medicherla
- Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| | - Carlos Fonck
- Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USA
| |
Collapse
|
|
6
|
Peterson AN, Hickerson LC, Pschirrer ER, Friend LB, Taub CC. Management of Friedreich Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature. Am J Cardiol 2024; 210:118-129. [PMID: 37838071 DOI: 10.1016/j.amjcard.2023.10.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/26/2023] [Accepted: 10/05/2023] [Indexed: 10/16/2023]
Abstract
A major manifestation of Friedreich ataxia (FRDA) is cardiomyopathy, caused by mitochondrial proliferation in myocytes. Because the lifespan for patients with FRDA improves with better treatment modalities, more patients are becoming pregnant, meaning that more medical providers must know how to care for this population. This report provides a review of the literature on multidisciplinary management of pregnant patients with FRDA and cardiomyopathy from preconception through lactation. A cardio-obstetrics team, including cardiology, anesthesiology, and obstetrics, should be involved for this entire period. All patients should be counseled on pregnancy risk using elements of existing stratification systems, and contraception should be discussed, highlighting the safety of intrauterine devices. Electrocardiogram should be obtained at baseline and each trimester, looking for atrial arrhythmias and ST-segment changes, as should transthoracic echocardiogram, with a focus on left ventricular ejection fraction-which is typically normal in FRDA cardiomyopathy-and relative wall thickness and global longitudinal strain-which tend to decrease as cardiomyopathy progresses. Brain natriuretic peptide is also a helpful marker to detect adverse events. If heart failure develops, it should be treated like any other etiology of heart failure during pregnancy. Atrial arrhythmias should be treated with β blockers or electrical cardioversion and anticoagulation, as necessary. Most patients with FRDA can deliver vaginally, and neuraxial analgesia is recommended during labor because of the risks associated with general anesthesia. Breastfeeding is encouraged, even for those taking cardiac medications.
Collapse
Affiliation(s)
- Ashleigh N Peterson
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Leigh C Hickerson
- Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - E Rebecca Pschirrer
- Department of Obstetrics and Gynecology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Lynsy B Friend
- Heart and Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Cynthia C Taub
- Department of Medicine, SUNY Upstate Medical University, Syracuse, New York.
| |
Collapse
|
|
7
|
Bouchard C, Gérard C, Yanyabé SGF, Majeau N, Aloui M, Buisson G, Yameogo P, Couture V, Tremblay JP. Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype. Genes (Basel) 2023; 14:1654. [PMID: 37628705 PMCID: PMC10454134 DOI: 10.3390/genes14081654] [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: 07/18/2023] [Revised: 08/09/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a GAA repeat in the intron 1 of the frataxin gene (FXN) leading to a lower expression of the frataxin protein. The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. We aimed to find an optimized mouse model with a phenotype comparable to the human patients to study the impact of therapy on the phenotype. We compared two mouse models: the YG8sR injected with an AAV. PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats. Both mouse models were compared to Y47R mice containing nine GAA repeats that were considered healthy mice. Behavior tests (parallel rod floor apparatus, hanging test, inverted T beam, and notched beam test) were carried out from 2 to 11 months and significant differences were noticed for both YG8sR mice injected with an anti-FXN shRNA and the YG8-800 mice compared to healthy mice. In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing an shRNA targeting frataxin does increase their phenotype. The YG8-800 mice have a phenotype comparable to the human ataxic phenotype.
Collapse
Affiliation(s)
- Camille Bouchard
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
- Département de Médecine Moléculaire, l’Université Laval Québec, Québec, QC G1V 4G2, Canada
| | - Catherine Gérard
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
- Département de Médecine Moléculaire, l’Université Laval Québec, Québec, QC G1V 4G2, Canada
| | - Solange Gni-fiene Yanyabé
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
- Département de Médecine Moléculaire, l’Université Laval Québec, Québec, QC G1V 4G2, Canada
| | - Nathalie Majeau
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
- Département de Médecine Moléculaire, l’Université Laval Québec, Québec, QC G1V 4G2, Canada
| | - Malek Aloui
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
| | - Gabrielle Buisson
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
| | - Pouiré Yameogo
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
- Département de Médecine Moléculaire, l’Université Laval Québec, Québec, QC G1V 4G2, Canada
| | - Vanessa Couture
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
- Département de Médecine Moléculaire, l’Université Laval Québec, Québec, QC G1V 4G2, Canada
| | - Jacques P. Tremblay
- Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, Canada (N.M.); (M.A.); (G.B.)
- Département de Médecine Moléculaire, l’Université Laval Québec, Québec, QC G1V 4G2, Canada
| |
Collapse
|
|
8
|
Yadav S, Waldeck-Weiermair M, Spyropoulos F, Bronson R, Pandey AK, Das AA, Sisti AC, Covington TA, Thulabandu V, Caplan S, Chutkow W, Steinhorn B, Michel T. Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress in chemogenetic transgenic mouse lines. Nat Commun 2023; 14:3094. [PMID: 37248315 PMCID: PMC10227029 DOI: 10.1038/s41467-023-38961-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 05/24/2023] [Indexed: 05/31/2023] Open
Abstract
Oxidative stress is associated with cardiovascular and neurodegenerative diseases. Here we report studies of neurovascular oxidative stress in chemogenetic transgenic mouse lines expressing yeast D-amino acid oxidase (DAAO) in neurons and vascular endothelium. When these transgenic mice are fed D-amino acids, DAAO generates hydrogen peroxide in target tissues. DAAO-TGCdh5 transgenic mice express DAAO under control of the putatively endothelial-specific Cdh5 promoter. When we provide these mice with D-alanine, they rapidly develop sensory ataxia caused by oxidative stress and mitochondrial dysfunction in neurons within dorsal root ganglia and nodose ganglia innervating the heart. DAAO-TGCdh5 mice also develop cardiac hypertrophy after chronic chemogenetic oxidative stress. This combination of ataxia, mitochondrial dysfunction, and cardiac hypertrophy is similar to findings in patients with Friedreich's ataxia. Our observations indicate that neurovascular oxidative stress is sufficient to cause sensory ataxia and cardiac hypertrophy. Studies of DAAO-TGCdh5 mice could provide mechanistic insights into Friedreich's ataxia.
Collapse
Affiliation(s)
- Shambhu Yadav
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Markus Waldeck-Weiermair
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Fotios Spyropoulos
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
- Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Roderick Bronson
- Department of Immunology, Harvard Medical School, Boston, MA, 02115, USA
| | - Arvind K Pandey
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Apabrita Ayan Das
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Alexander C Sisti
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Taylor A Covington
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Venkata Thulabandu
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Shari Caplan
- Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA
| | - William Chutkow
- Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA
| | - Benjamin Steinhorn
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Thomas Michel
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
| |
Collapse
|
|
9
|
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.
Collapse
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
| |
Collapse
|
|
10
|
Masingue M, Fernández-Eulate G, Debs R, Tard C, Labeyrie C, Leonard-Louis S, Dhaenens CM, Masson MA, Latour P, Stojkovic T. Strategy for genetic analysis in hereditary neuropathy. Rev Neurol (Paris) 2023; 179:10-29. [PMID: 36566124 DOI: 10.1016/j.neurol.2022.11.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/26/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022]
Abstract
Inherited neuropathies are a heterogeneous group of slowly progressive disorders affecting either motor, sensory, and/or autonomic nerves. Peripheral neuropathy may be the major component of a disease such as Charcot-Marie-Tooth disease or a feature of a more complex multisystemic disease involving the central nervous system and other organs. The goal of this review is to provide the clinical clues orientating the genetic diagnosis in a patient with inherited peripheral neuropathy. This review focuses on primary inherited neuropathies, amyloidosis, inherited metabolic diseases, while detailing clinical, neurophysiological and potential treatment of these diseases.
Collapse
Affiliation(s)
- M Masingue
- Centre de référence des maladies neuromusculaires Nord/Est/Île-de-France, hôpital Pitié-Salpêtrière, AP-HP, Paris, France.
| | - G Fernández-Eulate
- Centre de référence des maladies neuromusculaires Nord/Est/Île-de-France, hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| | - R Debs
- Service de neurophysiologie, hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| | - C Tard
- CHU de Lille, clinique neurologique, centre de référence des maladies neuromusculaires Nord/Est/Île-de-France, 59037 Lille cedex, France
| | - C Labeyrie
- Service de neurologie, hôpital Kremlin-Bicêtre, AP-HP, Le Kremlin-Bicêtre, France
| | - S Leonard-Louis
- Centre de référence des maladies neuromusculaires Nord/Est/Île-de-France, hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| | - C-M Dhaenens
- Université de Lille, Inserm, CHU de Lille, U1172-LilNCog-Lille Neuroscience & Cognition, 59000 Lille, France
| | - M A Masson
- Inserm U1127, Paris Brain Institute, ICM, Sorbonne Université, CNRS UMR 7225, hôpital Pitié-Salpêtrière, Paris, France
| | - P Latour
- Service de biochimie biologie moléculaire, CHU de Lyon, centre de biologie et pathologie Est, 69677 Bron cedex, France
| | - T Stojkovic
- Centre de référence des maladies neuromusculaires Nord/Est/Île-de-France, hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| |
Collapse
|
|
11
|
Role of cardiovascular magnetic resonance in the clinical evaluation of left ventricular hypertrophy: a 360° panorama. Int J Cardiovasc Imaging 2022; 39:793-809. [PMID: 36543912 DOI: 10.1007/s10554-022-02774-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 12/04/2022] [Indexed: 12/24/2022]
Abstract
Left ventricular hypertrophy (LVH) is a frequent imaging finding in the general population. In order to identify the precise etiology, a comprehensive diagnostic approach should be adopted, including the prevalence of each entity that may cause LVH, family history, clinical, electrocardiographic and imaging findings. By providing a detailed evaluation of the myocardium, cardiovascular magnetic resonance (CMR) has assumed a central role in the differential diagnosis of left ventricular hypertrophy, with the technique of parametric imaging allowing more refined tissue characterization. This article aims to establish a parallel between pathophysiological features and imaging findings through the broad spectrum of LVH entities, emphasizing the role of CMR in the differential diagnosis.
Collapse
|
|
12
|
Hohenfeld C, Terstiege U, Dogan I, Giunti P, Parkinson MH, Mariotti C, Nanetti L, Fichera M, Durr A, Ewenczyk C, Boesch S, Nachbauer W, Klopstock T, Stendel C, Rodríguez de Rivera Garrido FJ, Schöls L, Hayer SN, Klockgether T, Giordano I, Didszun C, Rai M, Pandolfo M, Rauhut H, Schulz JB, Reetz K. Prediction of the disease course in Friedreich ataxia. Sci Rep 2022; 12:19173. [PMID: 36357508 PMCID: PMC9649725 DOI: 10.1038/s41598-022-23666-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 11/03/2022] [Indexed: 11/11/2022] Open
Abstract
We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA.
Collapse
Affiliation(s)
- Christian Hohenfeld
- grid.1957.a0000 0001 0728 696XDepartment of Neurology, RWTH Aachen University, 52074 Aachen, Germany ,grid.1957.a0000 0001 0728 696XJARA Brain Institute Molecular Neuroscience and Neuroimaging, Research Centre Jülich and RWTH Aachen University, 52056 Aachen, Germany
| | - Ulrich Terstiege
- grid.1957.a0000 0001 0728 696XChair for Mathematics of Information Processing, RWTH Aachen University, 52062 Aachen, Germany
| | - Imis Dogan
- grid.1957.a0000 0001 0728 696XDepartment of Neurology, RWTH Aachen University, 52074 Aachen, Germany ,grid.1957.a0000 0001 0728 696XJARA Brain Institute Molecular Neuroscience and Neuroimaging, Research Centre Jülich and RWTH Aachen University, 52056 Aachen, Germany
| | - Paola Giunti
- grid.83440.3b0000000121901201Department of Clinical and Movement Neurosciences, Ataxia Centre, UCL-Queen Square Institute of Neurology, London, WC1N 3BG UK
| | - Michael H. Parkinson
- grid.83440.3b0000000121901201Department of Clinical and Movement Neurosciences, Ataxia Centre, UCL-Queen Square Institute of Neurology, London, WC1N 3BG UK
| | - Caterina Mariotti
- grid.417894.70000 0001 0707 5492Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Lorenzo Nanetti
- grid.417894.70000 0001 0707 5492Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Mario Fichera
- grid.417894.70000 0001 0707 5492Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy ,grid.7563.70000 0001 2174 1754PhD Program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Alexandra Durr
- grid.411439.a0000 0001 2150 9058Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, 75646 Paris, France
| | - Claire Ewenczyk
- grid.411439.a0000 0001 2150 9058Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, 75646 Paris, France
| | - Sylvia Boesch
- grid.5361.10000 0000 8853 2677Department of Neurology, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Wolfgang Nachbauer
- grid.5361.10000 0000 8853 2677Department of Neurology, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Thomas Klopstock
- grid.5252.00000 0004 1936 973XDepartment of Neurology, Friedrich Baur Institute, University Hospital, LMU, 80336 Munich, Germany ,grid.424247.30000 0004 0438 0426German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany ,grid.452617.3Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
| | - Claudia Stendel
- grid.5252.00000 0004 1936 973XDepartment of Neurology, Friedrich Baur Institute, University Hospital, LMU, 80336 Munich, Germany ,grid.424247.30000 0004 0438 0426German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
| | | | - Ludger Schöls
- grid.10392.390000 0001 2190 1447Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany ,grid.424247.30000 0004 0438 0426German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
| | - Stefanie N. Hayer
- grid.10392.390000 0001 2190 1447Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
| | - Thomas Klockgether
- grid.15090.3d0000 0000 8786 803XDepartment of Neurology, University Hospital of Bonn, 53127 Bonn, Germany ,grid.424247.30000 0004 0438 0426German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
| | - Ilaria Giordano
- grid.15090.3d0000 0000 8786 803XDepartment of Neurology, University Hospital of Bonn, 53127 Bonn, Germany
| | - Claire Didszun
- grid.1957.a0000 0001 0728 696XDepartment of Neurology, RWTH Aachen University, 52074 Aachen, Germany
| | - Myriam Rai
- grid.4989.c0000 0001 2348 0746Laboratory of Experimental Neurology, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Massimo Pandolfo
- grid.4989.c0000 0001 2348 0746Laboratory of Experimental Neurology, Université Libre de Bruxelles, 1070 Brussels, Belgium ,grid.14709.3b0000 0004 1936 8649Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 0G4 Canada
| | - Holger Rauhut
- grid.1957.a0000 0001 0728 696XChair for Mathematics of Information Processing, RWTH Aachen University, 52062 Aachen, Germany
| | - Jörg B. Schulz
- grid.1957.a0000 0001 0728 696XDepartment of Neurology, RWTH Aachen University, 52074 Aachen, Germany ,grid.1957.a0000 0001 0728 696XJARA Brain Institute Molecular Neuroscience and Neuroimaging, Research Centre Jülich and RWTH Aachen University, 52056 Aachen, Germany
| | - Kathrin Reetz
- grid.1957.a0000 0001 0728 696XDepartment of Neurology, RWTH Aachen University, 52074 Aachen, Germany ,grid.1957.a0000 0001 0728 696XJARA Brain Institute Molecular Neuroscience and Neuroimaging, Research Centre Jülich and RWTH Aachen University, 52056 Aachen, Germany
| |
Collapse
|
|
13
|
Groh WJ, Bhakta D, Tomaselli GF, Aleong RG, Teixeira RA, Amato A, Asirvatham SJ, Cha YM, Corrado D, Duboc D, Goldberger ZD, Horie M, Hornyak JE, Jefferies JL, Kääb S, Kalman JM, Kertesz NJ, Lakdawala NK, Lambiase PD, Lubitz SA, McMillan HJ, McNally EM, Milone M, Namboodiri N, Nazarian S, Patton KK, Russo V, Sacher F, Santangeli P, Shen WK, Sobral Filho DC, Stambler BS, Stöllberger C, Wahbi K, Wehrens XHT, Weiner MM, Wheeler MT, Zeppenfeld K. 2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders. Heart Rhythm 2022; 19:e61-e120. [PMID: 35500790 DOI: 10.1016/j.hrthm.2022.04.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 04/21/2022] [Indexed: 11/04/2022]
Abstract
This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by the Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs.
Collapse
Affiliation(s)
- William J Groh
- Ralph H. Johnson VA Medical Center and Medical University of South Carolina, Charleston, South Carolina
| | - Deepak Bhakta
- Indiana University School of Medicine, Indianapolis, Indiana
| | | | | | | | - Anthony Amato
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | | | | | - Domenico Corrado
- Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, Padova, Italy
| | - Denis Duboc
- Cardiology Department, Hôpital Cochin, AP-HP, Université de Paris, Paris, France
| | - Zachary D Goldberger
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Minoru Horie
- Shiga University of Medical Sciences, Otsu, Japan
| | | | | | - Stefan Kääb
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Jonathan M Kalman
- Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia
| | | | - Neal K Lakdawala
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Pier D Lambiase
- Barts Heart Centre, St Bartholomew's Hospital, University College London, and St Bartholomew's Hospital London, London, United Kingdom
| | | | - Hugh J McMillan
- Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada
| | | | | | - Narayanan Namboodiri
- Sree Chitra Institute for Medical Sciences and Technology, Thiruvananthapuram, India
| | | | | | | | - Frederic Sacher
- Bordeaux University Hospital, LIRYC Institute, Bordeaux, France
| | | | | | | | | | - Claudia Stöllberger
- Second Medical Department with Cardiology and Intensive Care Medicine, Klinik Landstraße, Vienna, Austria
| | - Karim Wahbi
- Cardiology Department, Hôpital Cochin, AP-HP, Université de Paris, Paris, France
| | | | | | | | | |
Collapse
|
|
14
|
Stokreef S, Lemos M, Quintas S. Importance of an echocardiogram in the evaluation of ataxia. BMJ Case Rep 2022; 15:e248691. [PMID: 35896307 PMCID: PMC9335040 DOI: 10.1136/bcr-2021-248691] [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] [Accepted: 07/14/2022] [Indexed: 11/03/2022] Open
Abstract
We present the case of a boy in his middle childhood with gait ataxia and loss of reflexes with a 1-year onset. He had a background of an autism spectrum disorder but was otherwise healthy. A paediatric cardiology assessment was requested to investigate possible cardiac involvement associated to his neurological symptoms. Even though he had no cardiac symptoms and a normal electrocardiography, the echocardiogram revealed severe asymmetric left ventricle hypertrophy consistent with hypertrophic cardiomyopathy. This prompted genetic testing and the diagnosis of Friedreich's ataxia was confirmed.
Collapse
Affiliation(s)
- Sarah Stokreef
- Pediatrics, Hospital do Divino Espirito Santo de Ponta Delgada EPE, Ponta Delgada, Portugal
| | - Mariana Lemos
- Pediatric Cardiology, Centro Hospitalar de Lisboa Ocidental EPE Hospital de Santa Cruz, Carnaxide, Portugal
| | - Sofia Quintas
- Pediatrics, Hospital de Santa Maria, Lisboa, Portugal
| |
Collapse
|
|
15
|
Neuromuscular diseases and their cardiac manifestations under the spectrum of cardiovascular imaging. Heart Fail Rev 2022; 27:2045-2058. [PMID: 35857244 DOI: 10.1007/s10741-022-10260-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/10/2022] [Indexed: 11/04/2022]
Abstract
Neuromuscular diseases (NMDs) include a broad spectrum of disorders that affect motor unit in every possible site, extending from the cell body of peripheral nerves to the muscle. The different lesion sites make this group of inherited disorders difficult to diagnose. Many NMDs, especially those involving skeletal muscles, can present significant cardiovascular complications, ranging from rhythm disturbances to the development of dilated or hypertrophic cardiomyopathy. Heart disease represents a major cause of morbidity and mortality among NMD patients, underlining the vital need for further familiarization with the pathogenesis and assessment of cardiac involvement. Cardiovascular imaging is the cornerstone for the evaluation of heart disorders in NMDs, with conventional echocardiography still offering a portable, affordable, and easily accessible solution. Meanwhile, newer echocardiographic techniques such as speckle tracking imaging in combination with cardiac magnetic resonance add new insights into further substrate characterization. The purpose of this review is to offer a brief presentation of the main NMDs and their cardiovascular complications, as well as the presentation of data that highlight the importance of cardiovascular imaging in early diagnosis, monitoring, and prognosis of these patients. Lastly, the authors provide a simple guide about which clinical features, imaging findings, and follow-up plan to adopt in each myopathic disorder.
Collapse
|
|
16
|
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.
Collapse
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.
| |
Collapse
|
|
17
|
Sivakumar A, Cherqui S. Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich's Ataxia. Front Genome Ed 2022; 4:903139. [PMID: 35663795 PMCID: PMC9157421 DOI: 10.3389/fgeed.2022.903139] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 04/21/2022] [Indexed: 12/26/2022] Open
Abstract
Friedreich's ataxia (FRDA) is an inherited, multisystemic disorder predominantly caused by GAA hyper expansion in intron 1 of frataxin (FXN) gene. This expansion mutation transcriptionally represses FXN, a mitochondrial protein that is required for iron metabolism and mitochondrial homeostasis, leading to neurodegerative and cardiac dysfunction. Current therapeutic options for FRDA are focused on improving mitochondrial function and increasing frataxin expression through pharmacological interventions but are not effective in delaying or preventing the neurodegeneration in clinical trials. Recent research on in vivo and ex vivo gene therapy methods in FRDA animal and cell models showcase its promise as a one-time therapy for FRDA. In this review, we provide an overview on the current and emerging prospects of gene therapy for FRDA, with specific focus on advantages of CRISPR/Cas9-mediated gene editing of FXN as a viable option to restore endogenous frataxin expression. We also assess the potential of ex vivo gene editing in hematopoietic stem and progenitor cells as a potential autologous transplantation therapeutic option and discuss its advantages in tackling FRDA-specific safety aspects for clinical translation.
Collapse
Affiliation(s)
| | - Stephanie Cherqui
- Division of Genetics, Department of Pediatrics, University of California, San Diego, San Diego, CA, United States
| |
Collapse
|
|
18
|
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.
Collapse
|
|
19
|
Pavez-Giani MG, Cyganek L. Recent Advances in Modeling Mitochondrial Cardiomyopathy Using Human Induced Pluripotent Stem Cells. Front Cell Dev Biol 2022; 9:800529. [PMID: 35083221 PMCID: PMC8784695 DOI: 10.3389/fcell.2021.800529] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 12/20/2021] [Indexed: 12/17/2022] Open
Abstract
Around one third of patients with mitochondrial disorders develop a kind of cardiomyopathy. In these cases, severity is quite variable ranging from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. ATP is primarily generated in the mitochondrial respiratory chain via oxidative phosphorylation by utilizing fatty acids and carbohydrates. Genes in both the nuclear and the mitochondrial DNA encode components of this metabolic route and, although mutations in these genes are extremely rare, the risk to develop cardiac symptoms is significantly higher in this patient cohort. Additionally, infants with cardiovascular compromise in mitochondrial deficiency display a worse late survival compared to patients without cardiac symptoms. At this point, the mechanisms behind cardiac disease progression related to mitochondrial gene mutations are poorly understood and current therapies are unable to substantially restore the cardiac performance and to reduce the disease burden. Therefore, new strategies are needed to uncover the pathophysiological mechanisms and to identify new therapeutic options for mitochondrial cardiomyopathies. Here, human induced pluripotent stem cell (iPSC) technology has emerged to provide a suitable patient-specific model system by recapitulating major characteristics of the disease in vitro, as well as to offer a powerful platform for pre-clinical drug development and for the testing of novel therapeutic options. In the present review, we summarize recent advances in iPSC-based disease modeling of mitochondrial cardiomyopathies and explore the patho-mechanistic insights as well as new therapeutic approaches that were uncovered with this experimental platform. Further, we discuss the challenges and limitations of this technology and provide an overview of the latest techniques to promote metabolic and functional maturation of iPSC-derived cardiomyocytes that might be necessary for modeling of mitochondrial disorders.
Collapse
Affiliation(s)
- Mario G Pavez-Giani
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany
| | - Lukas Cyganek
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany.,Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells", University of Göttingen, Göttingen, Germany
| |
Collapse
|
|
20
|
Rodríguez LR, Lapeña-Luzón T, Benetó N, Beltran-Beltran V, Pallardó FV, Gonzalez-Cabo P, Navarro JA. Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases? Antioxidants (Basel) 2022; 11:antiox11010165. [PMID: 35052668 PMCID: PMC8773297 DOI: 10.3390/antiox11010165] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum-mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich's ataxia, and Charcot-Marie-Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.
Collapse
Affiliation(s)
- Laura R. Rodríguez
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (T.L.-L.); (N.B.); (V.B.-B.); (F.V.P.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
- Correspondence: (L.R.R.); (P.G.-C.); (J.A.N.)
| | - Tamara Lapeña-Luzón
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (T.L.-L.); (N.B.); (V.B.-B.); (F.V.P.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - Noelia Benetó
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (T.L.-L.); (N.B.); (V.B.-B.); (F.V.P.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - Vicent Beltran-Beltran
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (T.L.-L.); (N.B.); (V.B.-B.); (F.V.P.)
| | - Federico V. Pallardó
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (T.L.-L.); (N.B.); (V.B.-B.); (F.V.P.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (T.L.-L.); (N.B.); (V.B.-B.); (F.V.P.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
- Correspondence: (L.R.R.); (P.G.-C.); (J.A.N.)
| | - Juan Antonio Navarro
- Department of Genetics, Universitat de València-INCLIVA, 46100 Valencia, Spain
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
- Correspondence: (L.R.R.); (P.G.-C.); (J.A.N.)
| |
Collapse
|
|
21
|
Iron Overload, Oxidative Stress, and Ferroptosis in the Failing Heart and Liver. Antioxidants (Basel) 2021; 10:antiox10121864. [PMID: 34942967 PMCID: PMC8698778 DOI: 10.3390/antiox10121864] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/20/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Iron accumulation is a key mediator of several cytotoxic mechanisms leading to the impairment of redox homeostasis and cellular death. Iron overload is often associated with haematological diseases which require regular blood transfusion/phlebotomy, and it represents a common complication in thalassaemic patients. Major damages predominantly occur in the liver and the heart, leading to a specific form of cell death recently named ferroptosis. Different from apoptosis, necrosis, and autophagy, ferroptosis is strictly dependent on iron and reactive oxygen species, with a dysregulation of mitochondrial structure/function. Susceptibility to ferroptosis is dependent on intracellular antioxidant capacity and varies according to the different cell types. Chemotherapy-induced cardiotoxicity has been proven to be mediated predominantly by iron accumulation and ferroptosis, whereas there is evidence about the role of ferritin in protecting cardiomyocytes from ferroptosis and consequent heart failure. Another paradigmatic organ for transfusion-associated complication due to iron overload is the liver, in which the role of ferroptosis is yet to be elucidated. Some studies report a role of ferroptosis in the initiation of hepatic inflammation processes while others provide evidence about an involvement in several pathologies including immune-related hepatitis and acute liver failure. In this manuscript, we aim to review the literature to address putative common features between the response to ferroptosis in the heart and liver. A better comprehension of (dys)similarities is pivotal for the development of future therapeutic strategies that can be designed to specifically target this type of cell death in an attempt to minimize iron-overload effects in specific organs.
Collapse
|
|
22
|
Parker LE, Landstrom AP. The clinical utility of pediatric cardiomyopathy genetic testing: From diagnosis to a precision medicine-based approach to care. PROGRESS IN PEDIATRIC CARDIOLOGY 2021; 62. [PMID: 34776723 DOI: 10.1016/j.ppedcard.2021.101413] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background Pediatric-onset cardiomyopathies are rare yet cause significant morbidity and mortality in affected children. Genetic testing has a major role in the clinical evaluation of pediatric-onset cardiomyopathies, and identification of a variant in an associated gene can be used to confirm the clinical diagnosis and exclude syndromic causes that may warrant different treatment strategies. Further, risk-predictive testing of first-degree relatives can assess who is at-risk of disease and requires continued clinical follow-up. Aim of Review In this review, we seek to describe the current role of genetic testing in the clinical diagnosis and management of patients and families with the five major cardiomyopathies. Further, we highlight the ongoing development of precision-based approaches to diagnosis, prognosis, and treatment. Key Scientific Concepts of Review Emerging application of genotype-phenotype correlations opens the door for genetics to guide a precision medicine-based approach to prognosis and potentially for therapies. Despite advances in our understanding of the genetic etiology of cardiomyopathy and increased accessibility of clinical genetic testing, not all pediatric cardiomyopathy patients have a clear genetic explanation for their disease. Expanded genomic studies are needed to understand the cause of disease in these patients, improve variant classification and genotype-driven prognostic predictions, and ultimately develop truly disease preventing treatment.
Collapse
Affiliation(s)
- Lauren E Parker
- Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, NC, United States
| | - Andrew P Landstrom
- Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, NC, United States.,Department of Cell Biology, Duke University School of Medicine, Durham, NC, United States
| |
Collapse
|
|
23
|
TAT for Enzyme/Protein Delivery to Restore or Destroy Cell Activity in Human Diseases. Life (Basel) 2021; 11:life11090924. [PMID: 34575072 PMCID: PMC8466028 DOI: 10.3390/life11090924] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/01/2021] [Accepted: 09/02/2021] [Indexed: 12/28/2022] Open
Abstract
Much effort has been dedicated in the recent decades to find novel protein/enzyme-based therapies for human diseases, the major challenge of such therapies being the intracellular delivery and reaching sub-cellular organelles. One promising approach is the use of cell-penetrating peptides (CPPs) for delivering enzymes/proteins into cells. In this review, we describe the potential therapeutic usages of CPPs (mainly trans-activator of transcription protein, TAT) in enabling the uptake of biologically active proteins/enzymes needed in cases of protein/enzyme deficiency, concentrating on mitochondrial diseases and on the import of enzymes or peptides in order to destroy pathogenic cells, focusing on cancer cells.
Collapse
|
|
24
|
Mazzaccara C, Mirra B, Barretta F, Caiazza M, Lombardo B, Scudiero O, Tinto N, Limongelli G, Frisso G. Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes. Int J Mol Sci 2021; 22:ijms22115742. [PMID: 34072184 PMCID: PMC8197938 DOI: 10.3390/ijms22115742] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/18/2021] [Accepted: 05/22/2021] [Indexed: 12/23/2022] Open
Abstract
Mitochondrial Cardiomyopathy (MCM) is a common manifestation of multi-organ Mitochondrial Diseases (MDs), occasionally present in non-syndromic cases. Diagnosis of MCM is complex because of wide clinical and genetic heterogeneity and requires medical, laboratory, and neuroimaging investigations. Currently, the molecular screening for MCM is fundamental part of MDs management and allows achieving the definitive diagnosis. In this article, we review the current genetic knowledge associated with MDs, focusing on diagnosis of MCM and MDs showing cardiac involvement. We searched for publications on mitochondrial and nuclear genes involved in MCM, mainly focusing on genetic screening based on targeted gene panels for the molecular diagnosis of the MCM, by using Next Generation Sequencing. Here we report twelve case reports, four case-control studies, eleven retrospective studies, and two prospective studies, for a total of twenty-nine papers concerning the evaluation of cardiac manifestations in mitochondrial diseases. From the analysis of published causal mutations, we identified 130 genes to be associated with mitochondrial heart diseases. A large proportion of these genes (34.3%) encode for key proteins involved in the oxidative phosphorylation system (OXPHOS), either as directly OXPHOS subunits (22.8%), and as OXPHOS assembly factors (11.5%). Mutations in several mitochondrial tRNA genes have been also reported in multi-organ or isolated MCM (15.3%). This review highlights the main disease-genes, identified by extensive genetic analysis, which could be included as target genes in next generation panels for the molecular diagnosis of patients with clinical suspect of mitochondrial cardiomyopathies.
Collapse
Affiliation(s)
- Cristina Mazzaccara
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (B.M.); (F.B.); (B.L.); (O.S.); (N.T.); (G.F.)
- CEINGE Advanced Biotechnologies, 80145 Naples, Italy
- Correspondence: ; Tel.: +39-0817-462-422
| | - Bruno Mirra
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (B.M.); (F.B.); (B.L.); (O.S.); (N.T.); (G.F.)
- CEINGE Advanced Biotechnologies, 80145 Naples, Italy
| | - Ferdinando Barretta
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (B.M.); (F.B.); (B.L.); (O.S.); (N.T.); (G.F.)
- CEINGE Advanced Biotechnologies, 80145 Naples, Italy
| | - Martina Caiazza
- Monaldi Hospital, AO Colli, 80131 Naples, Italy; (M.C.); (G.L.)
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, 80134 Naples, Italy
| | - Barbara Lombardo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (B.M.); (F.B.); (B.L.); (O.S.); (N.T.); (G.F.)
- CEINGE Advanced Biotechnologies, 80145 Naples, Italy
| | - Olga Scudiero
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (B.M.); (F.B.); (B.L.); (O.S.); (N.T.); (G.F.)
- CEINGE Advanced Biotechnologies, 80145 Naples, Italy
| | - Nadia Tinto
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (B.M.); (F.B.); (B.L.); (O.S.); (N.T.); (G.F.)
- CEINGE Advanced Biotechnologies, 80145 Naples, Italy
| | - Giuseppe Limongelli
- Monaldi Hospital, AO Colli, 80131 Naples, Italy; (M.C.); (G.L.)
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, 80134 Naples, Italy
| | - Giulia Frisso
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (B.M.); (F.B.); (B.L.); (O.S.); (N.T.); (G.F.)
- CEINGE Advanced Biotechnologies, 80145 Naples, Italy
| |
Collapse
|
|
25
|
Takazaki KAG, Quinaglia T, Venancio TD, Martinez ARM, Shah RV, Neilan TG, Jerosch-Herold M, Coelho-Filho OR, França MC. Pre-clinical left ventricular myocardial remodeling in patients with Friedreich's ataxia: A cardiac MRI study. PLoS One 2021; 16:e0246633. [PMID: 33770103 PMCID: PMC7996973 DOI: 10.1371/journal.pone.0246633] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 01/22/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Heart Failure (HF) is the most common cause of death in Friedreich's ataxia (FRDA), an inherited mitochondrial disease. Myocardial fibrosis and myocardial hypertrophy are well-documented autopsy features among FRDA patients with HF. OBJECTIVES To leverage the unique tissue characterization features of cardiac magnetic resonance (CMR) for characterizing myocardial remodeling in patients with genetically confirmed FRDA without HF and preserved left ventricular ejection fraction (LVEF > 55%). METHODS Twenty-seven FRDA's patients (age 27.6 ± 9.7 years, 15 women) and 10 healthy controls (32.6±7.3 years, 5 women) underwent a CMR for assessment of LV function, myocardial T1, late gadolinium enhancement (LGE), extracellular volume fraction (ECV), and intracellular water-lifetime (τic), a marker of cardiomyocyte size. RESULTS As compared to controls, FRDA patients had a preserved LVEF (LVEF: 70.5±7.4% vs. 63.9±9.0%, P<0.058), larger LV mass index (LVMASSi: 61±21.7 vs. 45±4.2g/m2, P<0.02), and decreased LV end-diastolic volume index (LVEDVi 53.1±12.0 vs. 75.7±16.1ml/m2, P<0.001), compared with controls. Additionally, ECV and cardiomyocyte size (τic,) were larger in FRDA patients (ECV: 0.36 ±0.05 vs. 0.25±0.02, P<0.001; τic: 0.15±0.08 vs. 0.06±0.03 s, P = 0.02). ECV and τic were positively associated with LV mass-to-volume ratio (ECV: r = 0.57, P = 0.003; τic: r = 0.39; P = 0.05). LVMASSi and cardiomyocyte mass-index [(1-ECV)·LVMASSi] declined with age at the CMR exam, independent of the age at initial diagnosis. CONCLUSIONS LV hypertrophy and concentric LV remodeling in FRDA are associated at the tissue level with an expansion of the ECV and an increase in cardiomyocyte size. The adverse tissue remodeling assessed by ECV and τic is associated with more severe cardiomyopathy classification, suggesting a role for these markers in tracking disease progression.
Collapse
Affiliation(s)
- Karen A. G. Takazaki
- Division of Medicine, Section of Neurology, Department of Neurology, School of Medical Sciences, University of Campinas – UNICAMP, Campinas, São Paulo, Brazil
| | - Thiago Quinaglia
- Division of Medicine, Section of Cardiology, Department of Internal Medicine, Division of Medicine, Section of Neurology, School of Medical Sciences, University of Campinas – UNICAMP, Campinas, São Paulo, Brazil
| | - Thiago D. Venancio
- Division of Medicine, Section of Neurology, Department of Neurology, School of Medical Sciences, University of Campinas – UNICAMP, Campinas, São Paulo, Brazil
| | - Alberto R. M. Martinez
- Division of Medicine, Section of Neurology, Department of Neurology, School of Medical Sciences, University of Campinas – UNICAMP, Campinas, São Paulo, Brazil
| | - Ravi V. Shah
- Division of Medicine, Section of Cardiovascular Imaging Research Program and Cardiac MR PET CT Program, Department of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Tomas G. Neilan
- Division of Medicine, Section of Cardiovascular Imaging Research Program and Cardiac MR PET CT Program, Department of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Michael Jerosch-Herold
- Division of Medicine, Section of MRI Physics, Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Otávio R. Coelho-Filho
- Division of Medicine, Section of Cardiology, Department of Internal Medicine, Division of Medicine, Section of Neurology, School of Medical Sciences, University of Campinas – UNICAMP, Campinas, São Paulo, Brazil
| | - Marcondes C. França
- Division of Medicine, Section of Neurology, Department of Neurology, School of Medical Sciences, University of Campinas – UNICAMP, Campinas, São Paulo, Brazil
| |
Collapse
|
|
26
|
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.
Collapse
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
| |
Collapse
|
|
27
|
Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. Emerging therapies in Friedreich's Ataxia. Expert Rev Neurother 2020; 20:1215-1228. [PMID: 32909841 PMCID: PMC8018609 DOI: 10.1080/14737175.2020.1821654] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 09/07/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Friedreich's ataxia (FRDA) is a progressive, neurodegenerative disease that results in gait and limb ataxia, diabetes, cardiac hypertrophy, and scoliosis. At the cellular level, FRDA results in the deficiency of frataxin, a mitochondrial protein that plays a vital role in iron homeostasis and amelioration of oxidative stress. No cure currently exists for FRDA, but exciting therapeutic developments which target different parts of the pathological cascade are on the horizon. AREAS COVERED Areas covered include past and emerging therapies for FRDA, including antioxidants and mitochondrial-related agents, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, deuterated polyunsaturated fatty acids, iron chelators, histone deacetylase (HDAC) inhibitors, trans-activator of transcription (TAT)-frataxin, interferon gamma (IFNγ), erythropoietin, resveratrol, gene therapy, and anti-sense oligonucleotides (ASOs), among others. EXPERT OPINION While drug discovery has been challenging, new and exciting prospective treatments for FRDA are currently on the horizon, including pharmaceutical agents and gene therapy. Agents that enhance mitochondrial function, such as Nrf2 activators, dPUFAs and catalytic antioxidants, as well as novel methods of frataxin augmentation and genetic modulation will hopefully provide treatment for this devastating disease.
Collapse
Affiliation(s)
- Theresa A. Zesiewicz
- University of South Florida (USF) Department of Neurology, USF Ataxia Research Center, Tampa Florida, James A Haley Veteran’s Hospital, Tampa, Florida, USA
| | - Joshua Hancock
- University of South Florida (USF) Department of Neurology, USF Ataxia Research Center, Tampa Florida, James A Haley Veteran’s Hospital, Tampa, Florida, USA
| | - Shaila D. Ghanekar
- University of South Florida (USF) Department of Neurology, USF Ataxia Research Center, Tampa Florida, James A Haley Veteran’s Hospital, Tampa, Florida, USA
| | - Sheng-Han Kuo
- Department of Neurology, Columbia University, New York, NY, USA
- Initiative for Columbia Ataxia and Tremor, New York, NY, USA
| | - Carlos A. Dohse
- Universidad Central Del Caribe School of Medicine, Bayamon, Puerto Rico
| | - Joshua Vega
- University of South Florida (USF) Department of Neurology, USF Ataxia Research Center, Tampa Florida, James A Haley Veteran’s Hospital, Tampa, Florida, USA
| |
Collapse
|
|
28
|
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.
Collapse
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
| |
Collapse
|
|
29
|
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.
Collapse
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.)
| |
Collapse
|
|
30
|
Bizzoca A, Caracciolo M, Corsi P, Magrone T, Jirillo E, Gennarini G. Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration. Molecules 2020; 25:E4085. [PMID: 32906751 PMCID: PMC7570916 DOI: 10.3390/molecules25184085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/28/2020] [Accepted: 09/02/2020] [Indexed: 11/16/2022] Open
Abstract
In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82-190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (β-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.
Collapse
Affiliation(s)
| | | | | | | | | | - Gianfranco Gennarini
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Medical School, University of Bari, Piazza Giulio Cesare, 11. I-70124 Bari, Italy; (A.B.); (M.C.); (P.C.); (T.M.); (E.J.)
| |
Collapse
|
|
31
|
Nuzhny EP, Abramycheva NY, Nikolaeva NS, Ershova MV, Klyushnikov SA, Illarioshkin SN, Fedotova EY. [Epigenetic regulation of clinical manifestations of Friedreich's disease]. Zh Nevrol Psikhiatr Im S S Korsakova 2020; 120:20-26. [PMID: 32105265 DOI: 10.17116/jnevro202012001120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
AIM To study a methylation profile of FXN gene and its influence on the clinical phenotype of Friedreich's desease (FD). MATERIAL AND METHODS The methylation pattern was analyzed in 17 patients with FD. Forty-five CpG-sites in the promoter region and the region of intron 1 of FXN: before the GAA-expansion (UP-GAA) and after the GAA-expansion (DOWN-GAA), were studied. RESULTS Correlations between the methylation level of CpG-sites in UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded FXN alleles in patients with FD were found. An analysis revealed an earlier onset and a more severe course of FD in cases with hypermethylation of several CpG-sites in the UP-GAA region. The correlation between the methylation pattern and the presence of extraneural manifestations of FD was also revealed. In FD patients with cardiomyopathy, a hypomethylated CpG-site in the promoter region was found. In FD patients with carbohydrate metabolism disorders, two hypomethylated CpG-sites in the DOWN-GAA region were observed. CONCLUSION The results indicate a significant contribution of epigenetic modifications of FXN to the clinical presentation of FA.
Collapse
Affiliation(s)
- E P Nuzhny
- Research Center of Neurology, Moscow, Russia
| | | | | | - M V Ershova
- Research Center of Neurology, Moscow, Russia
| | | | | | | |
Collapse
|
|
32
|
Tiano F, Amati F, Cherubini F, Morini E, Vancheri C, Maletta S, Fortuni S, Serio D, Quatrana A, Luffarelli R, Benini M, Alfedi G, Panarello L, Rufini A, Toschi N, Frontali M, Romano S, Marcotulli C, Casali C, Gioiosa S, Mariotti C, Mongelli A, Fichera M, Condò I, Novelli G, Testi R, Malisan F. Frataxin deficiency in Friedreich's ataxia is associated with reduced levels of HAX-1, a regulator of cardiomyocyte death and survival. Hum Mol Genet 2020; 29:471-482. [PMID: 31943004 DOI: 10.1093/hmg/ddz306] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/29/2019] [Accepted: 12/10/2019] [Indexed: 12/31/2022] Open
Abstract
Frataxin deficiency, responsible for Friedreich's ataxia (FRDA), is crucial for cell survival since it critically affects viability of neurons, pancreatic beta cells and cardiomyocytes. In FRDA, the heart is frequently affected with typical manifestation of hypertrophic cardiomyopathy, which can progress to heart failure and cause premature death. A microarray analysis performed on FRDA patient's lymphoblastoid cells stably reconstituted with frataxin, indicated HS-1-associated protein X-1 (HAX-1) as the most significantly upregulated transcript (FC = +2, P < 0.0006). quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and western blot analysis performed on (I) HEK293 stably transfected with empty vector compared to wild-type frataxin and (II) lymphoblasts from FRDA patients show that low frataxin mRNA and protein expression correspond to reduced levels of HAX-1. Frataxin overexpression and silencing were also performed in the AC16 human cardiomyocyte cell line. HAX-1 protein levels are indeed regulated through frataxin modulation. Moreover, correlation between frataxin and HAX-1 was further evaluated in peripheral blood mononuclear cells (PBMCs) from FRDA patients and from non-related healthy controls. A regression model for frataxin which included HAX-1, group membership and group* HAX-1 interaction revealed that frataxin and HAX-1 are associated both at mRNA and protein levels. Additionally, a linked expression of FXN, HAX-1 and antioxidant defence proteins MnSOD and Nrf2 was observed both in PBMCs and AC16 cardiomyocytes. Our results suggest that HAX-1 could be considered as a potential biomarker of cardiac disease in FRDA and the evaluation of its expression might provide insights into its pathogenesis as well as improving risk stratification strategies.
Collapse
Affiliation(s)
- Francesca Tiano
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Francesca Amati
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Department of Human Sciences and Quality of Life Promotion, University San Raffaele, 00166 Rome, Italy
| | - Fabio Cherubini
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Elena Morini
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Chiara Vancheri
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Sara Maletta
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Silvia Fortuni
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Dario Serio
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Andrea Quatrana
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Riccardo Luffarelli
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Monica Benini
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Giulia Alfedi
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Luca Panarello
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Alessandra Rufini
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Nicola Toschi
- Medical Physics Section, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- A.A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, MA 02129, USA
| | - Marina Frontali
- CNR Institute of Translational Pharmacology, 00133 Rome, Italy
| | - Silvia Romano
- Neurosciences, Mental Health and Sensory Organs (NESMOS) Department, Faculty of Medicine and Psychology, Sapienza University, 00189 Rome, Italy
| | - Christian Marcotulli
- Department of Medical Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University of Rome, 04100 Latina, Italy
| | - Carlo Casali
- Department of Medical Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University of Rome, 04100 Latina, Italy
| | - Silvia Gioiosa
- SCAI (Super Computing Applications and Innovations) CINECA, 00185 Rome, Italy
| | - Caterina Mariotti
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Alessia Mongelli
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Mario Fichera
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Ivano Condò
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Giuseppe Novelli
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Neuromed Institute, IRCCS, 86077 Pozzilli, Italy
| | - Roberto Testi
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Florence Malisan
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| |
Collapse
|
|
33
|
Jimenez-Tellez N, Greenway SC. Cellular models for human cardiomyopathy: What is the best option? World J Cardiol 2019; 11:221-235. [PMID: 31754410 PMCID: PMC6859298 DOI: 10.4330/wjc.v11.i10.221] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/17/2019] [Accepted: 09/22/2019] [Indexed: 02/06/2023] Open
Abstract
The genetic cardiomyopathies are a group of disorders related by abnormal myocardial structure and function. Although individually rare, these diseases collectively represent a significant health burden since they usually develop early in life and are a major cause of morbidity and mortality amongst affected children. The heterogeneity and rarity of these disorders requires the use of an appropriate model system in order to characterize the mechanism of disease and develop useful therapeutics since standard drug trials are infeasible. A common approach to study human disease involves the use of animal models, especially rodents, but due to important biological and physiological differences, this model system may not recapitulate human disease. An alternative approach for studying the metabolic cardiomyopathies relies on the use of cellular models which have most frequently been immortalized cell lines or patient-derived fibroblasts. However, the recent introduction of induced pluripotent stem cells (iPSCs), which have the ability to differentiate into any cell type in the body, is of great interest and has the potential to revolutionize the study of rare diseases. In this paper we review the advantages and disadvantages of each model system by comparing their utility for the study of mitochondrial cardiomyopathy with a particular focus on the use of iPSCs in cardiovascular biology for the modeling of rare genetic or metabolic diseases.
Collapse
Affiliation(s)
- Nerea Jimenez-Tellez
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Steven C Greenway
- Departments of Pediatrics, Cardiac Sciences, Biochemistry & Molecular Biology, Cumming School of Medicine, Libin Cardiovascular Institute of Alberta, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
| |
Collapse
|
|
34
|
Koeppen AH, Qian J, Travis AM, Sossei AB, Feustel PJ, Mazurkiewicz JE. Microvascular pathology in Friedreich cardiomyopathy. Histol Histopathol 2019; 35:39-46. [PMID: 31166002 DOI: 10.14670/hh-18-132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocyte hypertrophy, fiber necrosis, and inflammatory infiltration, sections show fibrosis and disorganized capillaries. We examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69. Immunohistochemistry with an antibody to CD34 allowed quantitative counts of capillary profiles for a comparison with cardiomyocyte counts in the same field. Capillary counts (mean±standard deviation [SD]) in normal controls were 1926±341/mm², while mean cardiomyocyte counts were 2003±686/mm². The median ratio of capillaries to cardiomyocytes was 1.0 (interquartile range [IQR]: 0.9-1.2). In FA, the number of cardiomyocytes/mm² was significantly less (704±361; p<0.001), and the median ratio of capillaries to heart fibers was 2.0 (IQR:1.4-2.4). There was a significant correlation of the expanded guanine-adenine-adenine trinucleotides (shorter allele, GAA1) with a younger age of onset, shorter disease duration, and lower cardiomyocyte counts. The ratio of capillaries to heart fibers was higher in patients with long GAA1 repeat expansions (e.g., 3.31 in GAA1 of 1200). Double-label immunofluorescence for CD34 and the fibroblast marker S100A4 revealed co-expression in endothelial cells, supporting endothelial-to-mesenchymal transition in the pathogenesis of cardiac fibrosis in FA. We propose that the pathogenesis of FA heart disease includes primary fibrosis.
Collapse
Affiliation(s)
- Arnulf H Koeppen
- Research Service, Veterans Affairs Medical Center, Albany, New York, USA. .,Department of Pathology, Albany Medical Center, Albany, New York, USA
| | - Jiang Qian
- Department of Pathology, Albany Medical Center, Albany, New York, USA
| | - Alicia M Travis
- Research Service, Veterans Affairs Medical Center, Albany, New York, USA
| | - Alyssa B Sossei
- Research Service, Veterans Affairs Medical Center, Albany, New York, USA
| | - Paul J Feustel
- Department of Neurosciences and Experimental Therapeutics, Albany Medical College, Albany, New York, USA
| | - Joseph E Mazurkiewicz
- Department of Neurosciences and Experimental Therapeutics, Albany Medical College, Albany, New York, USA
| |
Collapse
|
|
35
|
Llorens JV, Soriano S, Calap-Quintana P, Gonzalez-Cabo P, Moltó MD. The Role of Iron in Friedreich's Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models. Front Neurosci 2019; 13:75. [PMID: 30833885 PMCID: PMC6387962 DOI: 10.3389/fnins.2019.00075] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/23/2019] [Indexed: 12/12/2022] Open
Abstract
Friedreich's ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the proprioceptive pathways in the spinal cord, peripheral nerves and nuclei of the cerebellum. FRDA is an inherited disease with an autosomal recessive pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, which is an essential and highly evolutionary conserved protein whose deficit results in iron metabolism dysregulation and mitochondrial dysfunction. The first experimental evidence connecting frataxin with iron homeostasis came from Saccharomyces cerevisiae; iron accumulates in the mitochondria of yeast with deletion of the frataxin ortholog gene. This finding was soon linked to previous observations of iron deposits in the hearts of FRDA patients and was later reported in animal models of the disease. Despite advances made in the understanding of FRDA pathophysiology, the role of iron in this disease has not yet been completely clarified. Some of the questions still unresolved include the molecular mechanisms responsible for the iron accumulation and iron-mediated toxicity. Here, we review the contribution of the cellular and animal models of FRDA and relevance of the studies using FRDA patient samples to gain knowledge about these issues. Mechanisms of mitochondrial iron overload are discussed considering the potential roles of frataxin in the major mitochondrial metabolic pathways that use iron. We also analyzed the effect of iron toxicity on neuronal degeneration in FRDA by reactive oxygen species (ROS)-dependent and ROS-independent mechanisms. Finally, therapeutic strategies based on the control of iron toxicity are considered.
Collapse
Affiliation(s)
- José Vicente Llorens
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Sirena Soriano
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, United States
| | - Pablo Calap-Quintana
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain
- Center of Biomedical Network Research on Rare Diseases CIBERER, Valencia, Spain
- Associated Unit for Rare Diseases INCLIVA-CIPF, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - María Dolores Moltó
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
- Center of Biomedical Network Research on Mental Health CIBERSAM, Valencia, Spain
| |
Collapse
|
|
36
|
Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V. Heart disease in Friedreich’s ataxia. World J Cardiol 2019; 11:1-12. [PMID: 30705738 PMCID: PMC6354072 DOI: 10.4330/wjc.v11.i1.1] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/11/2018] [Accepted: 01/06/2019] [Indexed: 02/06/2023] Open
Abstract
Friedreich’s ataxia (FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify. The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and (less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life. However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length (i.e., markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-bound within 15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.
Collapse
Affiliation(s)
- Emily Hanson
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| | - Mark Sheldon
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| | - Brenda Pacheco
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| | - Mohammed Alkubeysi
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| | - Veena Raizada
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| |
Collapse
|
|
37
|
Cesar S. Neuromuscular diseases with hypertrophic cardiomyopathy. Glob Cardiol Sci Pract 2018; 2018:27. [PMID: 30393639 PMCID: PMC6209456 DOI: 10.21542/gcsp.2018.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 06/15/2018] [Indexed: 12/12/2022] Open
Abstract
[first paragraph of article]Neuromuscular disorders are frequently associated with cardiac abnormalities, even in pediatric population. Cardiac involvement includes both structural changes and conduction disease. In general, HCM is a rare manifestation of neuromuscular diseases. Autosomal dominant inheritance with mutations in sarcomeric genes are described in about 60% of young adults and adult population with HCM. Other genetic disorders, such as inherited metabolic and neuromuscular diseases and other chromosome abnormalities are responsible of 5–10% of HCM in adults. We review the most frequent neuromuscular diseases related with HCM.
Collapse
Affiliation(s)
- Sergi Cesar
- Arrhythmia, Inherited Cardiac Diseases and Sudden Death Unit, Pediatric Cardiology Department, Sant Joan de Déu Hospital and Sant Joan de Déu Research Institute, University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
38
|
Edenharter O, Schneuwly S, Navarro JA. Mitofusin-Dependent ER Stress Triggers Glial Dysfunction and Nervous System Degeneration in a Drosophila Model of Friedreich's Ataxia. Front Mol Neurosci 2018; 11:38. [PMID: 29563863 PMCID: PMC5845754 DOI: 10.3389/fnmol.2018.00038] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 01/29/2018] [Indexed: 11/13/2022] Open
Abstract
Friedreich's ataxia (FRDA) is the most important recessive ataxia in the Caucasian population. It is caused by a deficit of the mitochondrial protein frataxin. Despite its pivotal effect on biosynthesis of iron-sulfur clusters and mitochondrial energy production, little is known about the influence of frataxin depletion on homeostasis of the cellular mitochondrial network. We have carried out a forward genetic screen to analyze genetic interactions between genes controlling mitochondrial homeostasis and Drosophila frataxin. Our screen has identified silencing of Drosophila mitofusin (Marf) as a suppressor of FRDA phenotypes in glia. Drosophila Marf is known to play crucial roles in mitochondrial fusion, mitochondrial degradation and in the interface between mitochondria and endoplasmic reticulum (ER). Thus, we have analyzed the effects of frataxin knockdown on mitochondrial morphology, mitophagy and ER function in our fly FRDA model using different histological and molecular markers such as tetramethylrhodamine, ethyl ester (TMRE), mitochondria-targeted GFP (mitoGFP), p62, ATG8a, LAMP1, Xbp1 and BiP/GRP78. Furthermore, we have generated the first Drosophila transgenic line containing the mtRosella construct under the UAS control to study the progression of the mitophagy process in vivo. Our results indicated that frataxin-deficiency had a small impact on mitochondrial morphology but enhanced mitochondrial clearance and altered the ER stress response in Drosophila. Remarkably, we demonstrate that downregulation of Marf suppresses ER stress in frataxin-deficient cells and this is sufficient to improve locomotor dysfunction, brain degeneration and lipid dyshomeostasis in our FRDA model. In agreement, chemical reduction of ER stress by means of two different compounds was sufficient to ameliorate the effects of frataxin deficiency in three different fly FRDA models. Altogether, our results strongly suggest that the protection mediated by Marf knockdown in glia is mainly linked to its role in the mitochondrial-ER tethering and not to mitochondrial dynamics or mitochondrial degradation and that ER stress is a novel and pivotal player in the progression and etiology of FRDA. This work might define a new pathological mechanism in FRDA, linking mitochondrial dysfunction due to frataxin deficiency and mitofusin-mediated ER stress, which might be responsible for characteristic cellular features of the disease and also suggests ER stress as a therapeutic target.
Collapse
Affiliation(s)
- Oliver Edenharter
- Department of Developmental Biology, Institute of Zoology, University of Regensburg, Regensburg, Germany
| | - Stephan Schneuwly
- Department of Developmental Biology, Institute of Zoology, University of Regensburg, Regensburg, Germany
| | - Juan A. Navarro
- Department of Developmental Biology, Institute of Zoology, University of Regensburg, Regensburg, Germany
| |
Collapse
|
|
39
|
Wang Q, Guo L, Strawser CJ, Hauser LA, Hwang WT, Snyder NW, Lynch DR, Mesaros C, Blair IA. Low apolipoprotein A-I levels in Friedreich's ataxia and in frataxin-deficient cells: Implications for therapy. PLoS One 2018; 13:e0192779. [PMID: 29447225 PMCID: PMC5813973 DOI: 10.1371/journal.pone.0192779] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 01/30/2018] [Indexed: 12/21/2022] Open
Abstract
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.
Collapse
Affiliation(s)
- QingQing Wang
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Penn SRP Center and Center of Excellence in Environmental Toxicology Center, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Lili Guo
- Penn SRP Center and Center of Excellence in Environmental Toxicology Center, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Cassandra J. Strawser
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Lauren A. Hauser
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Nathaniel W. Snyder
- AJ Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania, United States of America
| | - David R. Lynch
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Clementina Mesaros
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Penn SRP Center and Center of Excellence in Environmental Toxicology Center, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Ian A. Blair
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Penn SRP Center and Center of Excellence in Environmental Toxicology Center, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, United States of America
| |
Collapse
|
|
40
|
Rocca CJ, Goodman SM, Dulin JN, Haquang JH, Gertsman I, Blondelle J, Smith JLM, Heyser CJ, Cherqui S. Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich's ataxia. Sci Transl Med 2017; 9:eaaj2347. [PMID: 29070698 PMCID: PMC5735830 DOI: 10.1126/scitranslmed.aaj2347] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 01/31/2017] [Accepted: 06/13/2017] [Indexed: 12/14/2022]
Abstract
Friedreich's ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.
Collapse
Affiliation(s)
- Celine J Rocca
- Division of Genetics, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Spencer M Goodman
- Division of Genetics, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jennifer N Dulin
- Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Joseph H Haquang
- Division of Genetics, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Ilya Gertsman
- Division of Genetics, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jordan Blondelle
- Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Janell L M Smith
- Division of Genetics, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Charles J Heyser
- Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Stephanie Cherqui
- Division of Genetics, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
| |
Collapse
|
|
41
|
Abstract
PURPOSE OF REVIEW Mitochondrial disorders are an increasingly recognized cause of heart dysfunction, with the primary manifestations being cardiomyopathy and conduction defects. This review focuses on the complex genetics of mitochondrial disease and recently discovered conditions that affect mitochondrial function. RECENT FINDINGS Next-generation sequencing techniques, especially whole-exome sequencing, have led to the discovery of a number of conditions that cause mitochondrial dysfunction and subsequent cardiac abnormalities. Nuclear DNA defects are the main cause of mitochondrial disease in children, with disease pathogenesis being related to either abnormalities in specific mitochondrial electron transport chain subunits or in proteins related to subunit or mitochondrial DNA maintenance, mitochondrial protein translation, lipid bilayer structure, or other aspects of mitochondrial function. SUMMARY Currently, symptomatic therapy using standard medications targeting relief of complications is the primary approach to treatment. There are no US Food and Drug Administration-approved therapies for the specific treatment of mitochondrial disease. However, on the basis of recent advances in understanding of the pathophysiology of these complex disorders, various novel approaches are either in clinical trials or in development.
Collapse
Affiliation(s)
- Gregory M Enns
- Department of Pediatrics, Stanford University, Stanford, California, USA
| |
Collapse
|
|
42
|
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.
Collapse
Affiliation(s)
- Roger W Byard
- 1 The University of Adelaide Medical School, Australia
- 2 Forensic Science SA, Australia
| | | |
Collapse
|
|
43
|
Feingold B, Mahle WT, Auerbach S, Clemens P, Domenighetti AA, Jefferies JL, Judge DP, Lal AK, Markham LW, Parks WJ, Tsuda T, Wang PJ, Yoo SJ. Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association. Circulation 2017; 136:e200-e231. [DOI: 10.1161/cir.0000000000000526] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
44
|
Martin AS, Abraham DM, Hershberger KA, Bhatt DP, Mao L, Cui H, Liu J, Liu X, Muehlbauer MJ, Grimsrud PA, Locasale JW, Payne RM, Hirschey MD. Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model. JCI Insight 2017; 2:93885. [PMID: 28724806 DOI: 10.1172/jci.insight.93885] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 06/06/2017] [Indexed: 12/23/2022] Open
Abstract
Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich's ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3-KO and SIRT3-KO/FXN-KO (double KO [dKO]) models. The improvement in cardiac function upon NMN treatment in the FXN-KO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio-protection, SIRT3 mediates NMN-induced improvements in both cardiac and extracardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich's ataxia patients.
Collapse
Affiliation(s)
- Angelical S Martin
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center.,Department of Pharmacology and Cancer Biology
| | - Dennis M Abraham
- Department of Medicine, Division of Cardiology and Duke Cardiovascular Physiology Core, Duke University Medical Center, Durham, North Carolina, USA
| | - Kathleen A Hershberger
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center.,Department of Pharmacology and Cancer Biology
| | - Dhaval P Bhatt
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center
| | - Lan Mao
- Department of Medicine, Division of Cardiology and Duke Cardiovascular Physiology Core, Duke University Medical Center, Durham, North Carolina, USA
| | - Huaxia Cui
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center
| | - Juan Liu
- Department of Pharmacology and Cancer Biology
| | | | - Michael J Muehlbauer
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center
| | - Paul A Grimsrud
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center
| | - Jason W Locasale
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center.,Department of Pharmacology and Cancer Biology
| | - R Mark Payne
- Department of Medicine, Division of Pediatrics, Indiana University, Indianapolis, Indiana, USA
| | - Matthew D Hirschey
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center.,Department of Pharmacology and Cancer Biology.,Department of Medicine, Division of Endocrinology, Metabolism, & Nutrition, Duke University Medical Center, Durham, North Carolina, USA
| |
Collapse
|
|
45
|
Crombie DE, Curl CL, Raaijmakers AJA, Sivakumaran P, Kulkarni T, Wong RCB, Minami I, Evans-Galea MV, Lim SY, Delbridge L, Corben LA, Dottori M, Nakatsuji N, Trounce IA, Hewitt AW, Delatycki MB, Pera MF, Pébay A. Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency. Aging (Albany NY) 2017; 9:1440-1452. [PMID: 28562313 PMCID: PMC5472743 DOI: 10.18632/aging.101247] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 05/27/2017] [Indexed: 01/12/2023]
Abstract
We sought to identify the impacts of Friedreich's ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes. FRDA iPSC- cardiomyocytes retained low levels of FRATAXIN (FXN) mRNA and protein. Electrophysiology revealed an increased variation of FRDA- cardiomyocyte beating rates which was prevented by addition of nifedipine, suggestive of a calcium handling deficiency. Finally, calcium imaging was performed and we identified small amplitude, diastolic and systolic calcium transients confirming a deficiency in calcium handling. We defined a robust FRDA cardiac-specific electrophysiological profile in patient-derived iPSCs which could be used for high throughput compound screening. This cell-specific signature will contribute to the identification and screening of novel treatments for this life-threatening disease.
Collapse
Affiliation(s)
- Duncan E. Crombie
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Claire L. Curl
- Department of Physiology, the University of Melbourne, Melbourne, Australia
| | | | | | - Tejal Kulkarni
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
- Centre for Neural Engineering & Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia
| | - Raymond CB Wong
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Itsunari Minami
- Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan
| | - Marguerite V. Evans-Galea
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, and Department of Paediatrics, The University of Melbourne, Melbourne, Australia
| | - Shiang Y. Lim
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
- O'Brien Institute Department, St Vincent Institute of Medical Research, Fitzroy, Australia
| | - Lea Delbridge
- O'Brien Institute Department, St Vincent Institute of Medical Research, Fitzroy, Australia
| | - Louise A. Corben
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, and Department of Paediatrics, The University of Melbourne, Melbourne, Australia
- School of Psychological Sciences, Monash University, Frankston, Australia
| | - Mirella Dottori
- Centre for Neural Engineering & Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia
| | - Norio Nakatsuji
- Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan
| | - Ian A. Trounce
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Alex W. Hewitt
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
- Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Australia
| | - Martin B. Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, and Department of Paediatrics, The University of Melbourne, Melbourne, Australia
- School of Psychological Sciences, Monash University, Frankston, Australia
- Victorian Clinical Genetics Services, Parkville, Australia
| | - Martin F. Pera
- Department of Anatomy and Neurosciences, the University of Melbourne, Florey Neuroscience & Mental Health Institute, Walter and Eliza Hall Institute of Medical Research, Australia
| | - Alice Pébay
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| |
Collapse
|
|
46
|
Shah R, Nucifora G, Perry R, Selvanayagam JB. Noninvasive imaging in cardiac deposition diseases. J Magn Reson Imaging 2017; 47:44-59. [DOI: 10.1002/jmri.25720] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 03/16/2017] [Indexed: 01/13/2023] Open
Affiliation(s)
- Ranjit Shah
- Department of Cardiovascular Medicine; Flinders Medical Centre; Bedford Park Adelaide Australia
- Department of Heart Health; South Australian Health & Medical Research Institute; Adelaide Australia
| | - Gaetano Nucifora
- Department of Heart Health; South Australian Health & Medical Research Institute; Adelaide Australia
- School of Medicine; Flinders University; Bedford Park Adelaide Australia
| | - Rebecca Perry
- Department of Cardiovascular Medicine; Flinders Medical Centre; Bedford Park Adelaide Australia
- Department of Heart Health; South Australian Health & Medical Research Institute; Adelaide Australia
- School of Medicine; Flinders University; Bedford Park Adelaide Australia
| | - Joseph B. Selvanayagam
- Department of Cardiovascular Medicine; Flinders Medical Centre; Bedford Park Adelaide Australia
- Department of Heart Health; South Australian Health & Medical Research Institute; Adelaide Australia
- School of Medicine; Flinders University; Bedford Park Adelaide Australia
| |
Collapse
|
|
47
|
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.
Collapse
Affiliation(s)
- Katrin Bürk
- University of Marburg, and Paracelsus-Elena Klinik, Klinikstr. 16, 34128 Kassel, Germany
| |
Collapse
|
|
48
|
Vogel AP, Wardrop MI, Folker JE, Synofzik M, Corben LA, Delatycki MB, Awan SN. Voice in Friedreich Ataxia. J Voice 2017; 31:243.e9-243.e19. [DOI: 10.1016/j.jvoice.2016.04.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 04/26/2016] [Accepted: 04/27/2016] [Indexed: 10/21/2022]
|
|
49
|
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.
Collapse
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.
| |
Collapse
|
|
50
|
Sommerville RB, Vincenti MG, Winborn K, Casey A, Stitziel NO, Connolly AM, Mann DL. Diagnosis and management of adult hereditary cardio-neuromuscular disorders: A model for the multidisciplinary care of complex genetic disorders. Trends Cardiovasc Med 2017; 27:51-58. [DOI: 10.1016/j.tcm.2016.06.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 06/06/2016] [Accepted: 06/08/2016] [Indexed: 01/16/2023]
|