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Quatrana A, Petrillo S, Torda C, De Santis E, Bertini E, Piemonte F. Redox homeostasis and inflammation in fibroblasts of patients with Friedreich Ataxia: a possible cross talk. Front Mol Neurosci 2025; 18:1571402. [PMID: 40308559 PMCID: PMC12041223 DOI: 10.3389/fnmol.2025.1571402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
Redox homeostasis is impaired in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2, the master regulator of tissue redox balance, is defective in the disease, driving cells to ferroptosis. Neuro-inflammation is recently emerging as an additional pathological mechanism in FRDA and has to be understood in order to go deeper into the pathogenesis of the disease. As a functional cross talk between Nrf2 and NF-kB pathways has been previously reported, we wonder if inflammation may be activated in FRDA as a consequence of Nrf2 deficiency. Thus, we analyzed the expression of proteins involved in the antioxidant and inflammatory responses in fibroblasts of patients with FRDA. We found a significant activation of the TLR4/NF-kB/IL-1β axis in patients, associated to a consistent increase of the redox enzymes thioredoxin 1 (TRX1) and glutaredoxin 1 (GLRX1), which are essential to activate NF-kB under oxidative stress conditions. Furthermore, we investigated the role of 4-HNE, a by-product of lipid peroxidation, as a potential mediator between ferroptosis and inflammation in FRDA.
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Affiliation(s)
- Andrea Quatrana
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Sara Petrillo
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Caterina Torda
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Eleonora De Santis
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Enrico Bertini
- Research Unit of Neuromuscular Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Fiorella Piemonte
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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Ercanbrack WS, Ramirez M, Dungan A, Gaul E, Ercanbrack SJ, Wingert RA. Frataxin deficiency and the pathology of Friedreich's Ataxia across tissues. Tissue Barriers 2025:2462357. [PMID: 39981684 DOI: 10.1080/21688370.2025.2462357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 01/08/2025] [Accepted: 01/14/2025] [Indexed: 02/22/2025] Open
Abstract
Friedreich's Ataxia (FRDA) is a neurodegenerative disease that affects a variety of different organ systems. The disease is caused by GAA repeat expansions in intron 1 of the Frataxin gene (FXN), which results in a decrease in the expression of the FXN protein. FXN is needed for the biogenesis of iron-sulfur clusters (ISC) which are required by key metabolic processes in the mitochondria. Without ISCs those processes do not occur properly. As a result, reactive oxygen species accumulate, and the mitochondria cease to function. Iron is also thought to accumulate in the cells of certain tissue types. These processes are thought to be intimately related to the pathologies affecting a myriad of tissues in FRDA. Most FRDA patients suffer from loss of motor control, cardiomyopathy, scoliosis, foot deformities, and diabetes. In this review, we discuss the known features of FRDA pathology and the current understanding about the basis of these alterations.
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Affiliation(s)
- Wesley S Ercanbrack
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Mateo Ramirez
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Austin Dungan
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Ella Gaul
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Sarah J Ercanbrack
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Rebecca A Wingert
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
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Grander M, Haschka D, Indelicato E, Kremser C, Amprosi M, Nachbauer W, Henninger B, Stefani A, Högl B, Fischer C, Seifert M, Kiechl S, Weiss G, Boesch S. Genetic Determined Iron Starvation Signature in Friedreich's Ataxia. Mov Disord 2024; 39:1088-1098. [PMID: 38686449 DOI: 10.1002/mds.29819] [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: 12/28/2023] [Revised: 04/02/2024] [Accepted: 04/09/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking. OBJECTIVES The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients. METHODS In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R2*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1). RESULTS We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R2*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R2* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria. CONCLUSIONS We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Manuel Grander
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - David Haschka
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Elisabetta Indelicato
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Kremser
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Matthias Amprosi
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Wolfgang Nachbauer
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Benjamin Henninger
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Ambra Stefani
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Birgit Högl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christine Fischer
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Seifert
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Kiechl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- VASCage, Centre on Clinical Stroke Research, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Sylvia Boesch
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Harding IH, Nur Karim MI, Selvadurai LP, Corben LA, Delatycki MB, Monti S, Saccà F, Georgiou-Karistianis N, Cocozza S, Egan GF. Localized Changes in Dentate Nucleus Shape and Magnetic Susceptibility in Friedreich Ataxia. Mov Disord 2024; 39:1109-1118. [PMID: 38644761 DOI: 10.1002/mds.29816] [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: 11/13/2023] [Revised: 03/07/2024] [Accepted: 04/01/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND The dentate nuclei of the cerebellum are key sites of neuropathology in Friedreich ataxia (FRDA). Reduced dentate nucleus volume and increased mean magnetic susceptibility, a proxy of iron concentration, have been reported by magnetic resonance imaging studies in people with FRDA. Here, we investigate whether these changes are regionally heterogeneous. METHODS Quantitative susceptibility mapping data were acquired from 49 people with FRDA and 46 healthy controls. The dentate nuclei were manually segmented and analyzed using three dimensional vertex-based shape modeling and voxel-based assessments to identify regional changes in morphometry and susceptibility, respectively. RESULTS Individuals with FRDA, relative to healthy controls, showed significant bilateral surface contraction most strongly at the rostral and caudal boundaries of the dentate nuclei. The magnitude of this surface contraction correlated with disease duration, and to a lesser extent, ataxia severity. Significantly greater susceptibility was also evident in the FRDA cohort relative to controls, but was instead localized to bilateral dorsomedial areas, and also correlated with disease duration and ataxia severity. CONCLUSIONS Changes in the structure of the dentate nuclei in FRDA are not spatially uniform. Atrophy is greatest in areas with high gray matter density, whereas increases in susceptibility-reflecting iron concentration, demyelination, and/or gliosis-predominate in the medial white matter. These findings converge with established histological reports and indicate that regional measures of dentate nucleus substructure are more sensitive measures of disease expression than full-structure averages. Biomarker development and therapeutic strategies that directly target the dentate nuclei, such as gene therapies, may be optimized by targeting these areas of maximal pathology. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Ian H Harding
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Muhammad Ikhsan Nur Karim
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
- Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Louisa P Selvadurai
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Louise A Corben
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Australia
- Department of Pediatrics, University of Melbourne, Parkville, Australia
- Turner Institute for Brain and Mental Health and School of Psychological Sciences, Monash University, Melbourne, Australia
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Australia
- Department of Pediatrics, University of Melbourne, Parkville, Australia
| | - Serena Monti
- Institute of Biostructure and Bioimaging, National Research Council, Naples, Italy
| | - Francesco Saccà
- Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples "Federico II", Naples, Italy
| | - Nellie Georgiou-Karistianis
- Turner Institute for Brain and Mental Health and School of Psychological Sciences, Monash University, Melbourne, Australia
| | - Sirio Cocozza
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples, Italy
| | - Gary F Egan
- Monash Biomedical Imaging, Monash University, Melbourne, Australia
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Jäschke D, Steiner KM, Chang DI, Claaßen J, Uslar E, Thieme A, Gerwig M, Pfaffenrot V, Hulst T, Gussew A, Maderwald S, Göricke SL, Minnerop M, Ladd ME, Reichenbach JR, Timmann D, Deistung A. Age-related differences of cerebellar cortex and nuclei: MRI findings in healthy controls and its application to spinocerebellar ataxia (SCA6) patients. Neuroimage 2023; 270:119950. [PMID: 36822250 DOI: 10.1016/j.neuroimage.2023.119950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 02/06/2023] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Understanding cerebellar alterations due to healthy aging provides a reference point against which pathological findings in late-onset disease, for example spinocerebellar ataxia type 6 (SCA6), can be contrasted. In the present study, we investigated the impact of aging on the cerebellar nuclei and cerebellar cortex in 109 healthy controls (age range: 16 - 78 years) using 3 Tesla magnetic resonance imaging (MRI). Findings were compared with 25 SCA6 patients (age range: 38 - 78 years). A subset of 16 SCA6 (included: 14) patients and 50 controls (included: 45) received an additional MRI scan at 7 Tesla and were re-scanned after one year. MRI included T1-weighted, T2-weighted FLAIR, and multi-echo T2*-weighted imaging. The T2*-weighted phase images were converted to quantitative susceptibility maps (QSM). Since the cerebellar nuclei are characterized by elevated iron content with respect to their surroundings, two independent raters manually outlined them on the susceptibility maps. T1-weighted images acquired at 3T were utilized to automatically identify the cerebellar gray matter (GM) volume. Linear correlations revealed significant atrophy of the cerebellum due to tissue loss of cerebellar cortical GM in healthy controls with increasing age. Reduction of the cerebellar GM was substantially stronger in SCA6 patients. The volume of the dentate nuclei did not exhibit a significant relationship with age, at least in the age range between 18 and 78 years, whereas mean susceptibilities of the dentate nuclei increased with age. As previously shown, the dentate nuclei volumes were smaller and magnetic susceptibilities were lower in SCA6 patients compared to age- and sex-matched controls. The significant dentate volume loss in SCA6 patients could also be confirmed with 7T MRI. Linear mixed effects models and individual paired t-tests accounting for multiple comparisons revealed no statistical significant change in volume and susceptibility of the dentate nuclei after one year in neither patients nor controls. Importantly, dentate volumes were more sensitive to differentiate between SCA6 (Cohen's d = 3.02) and matched controls than the cerebellar cortex volume (d = 2.04). In addition to age-related decline of the cerebellar cortex and atrophy in SCA6 patients, age-related increase of susceptibility of the dentate nuclei was found in controls, whereas dentate volume and susceptibility was significantly decreased in SCA6 patients. Because no significant changes of any of these parameters was found at follow-up, these measures do not allow to monitor disease progression at short intervals.
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Affiliation(s)
- Dominik Jäschke
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany; Department of Radiology and Nuclear Medicine, University Hospital Basel, Basel 4031, Switzerland
| | - Katharina M Steiner
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany; LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Duisburg-Essen, Essen 45147, Germany
| | - Dae-In Chang
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany; Clinic for Psychiatry, Psychotherapy and Preventive Medicine, LWL-University Hospital of the Ruhr-University Bochum, Bochum 44791, Germany
| | - Jens Claaßen
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany; Fachklinik für Neurologie, MEDICLIN Klinik Reichshof, Reichshof-Eckenhagen 51580, Germany
| | - Ellen Uslar
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany
| | - Andreas Thieme
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany
| | - Marcus Gerwig
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany
| | - Viktor Pfaffenrot
- Erwin L. Hahn Institute for Magnetic Resonance Imaging, University of Duisburg-Essen, Essen 45141, Germany
| | - Thomas Hulst
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany; Erasmus University College, Rotterdam 3011 HP, the Netherlands
| | - Alexander Gussew
- University Clinic and Outpatient Clinic for Radiology, Department for Radiation Medicine, University Hospital Halle (Saale), Ernst-Grube-Str. 40, Halle (Saale) 06120, Germany
| | - Stefan Maderwald
- Erwin L. Hahn Institute for Magnetic Resonance Imaging, University of Duisburg-Essen, Essen 45141, Germany
| | - Sophia L Göricke
- Institute of Diagnostic and Interventional Neuroradiology, Essen University Hospital, University of Duisburg-Essen, Essen 45141, Germany
| | - Martina Minnerop
- Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich 52425, Germany; Department of Neurology, Center for Movement Disorders and Neuromodulation, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf 40225, Germany; Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf 40225, Germany
| | - Mark E Ladd
- Erwin L. Hahn Institute for Magnetic Resonance Imaging, University of Duisburg-Essen, Essen 45141, Germany; Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Faculty of Physics and Astronomy and Faculty of Medicine, Heidelberg University, Heidelberg 69120, Germany
| | - Jürgen R Reichenbach
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena 07743, Germany
| | - Dagmar Timmann
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany; Erwin L. Hahn Institute for Magnetic Resonance Imaging, University of Duisburg-Essen, Essen 45141, Germany
| | - Andreas Deistung
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen 45147, Germany; University Clinic and Outpatient Clinic for Radiology, Department for Radiation Medicine, University Hospital Halle (Saale), Ernst-Grube-Str. 40, Halle (Saale) 06120, Germany; Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena 07743, Germany.
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Costa I, Barbosa DJ, Benfeito S, Silva V, Chavarria D, Borges F, Remião F, Silva R. Molecular mechanisms of ferroptosis and their involvement in brain diseases. Pharmacol Ther 2023; 244:108373. [PMID: 36894028 DOI: 10.1016/j.pharmthera.2023.108373] [Citation(s) in RCA: 157] [Impact Index Per Article: 78.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023]
Abstract
Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways. Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors. Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors. Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.
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Affiliation(s)
- Inês Costa
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Daniel José Barbosa
- TOXRUN - Toxicology Research Unit, Department of Sciences, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal
| | - Sofia Benfeito
- CIQUP-IMS - Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal.
| | - Vera Silva
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; CIQUP-IMS - Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Daniel Chavarria
- CIQUP-IMS - Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Fernanda Borges
- CIQUP-IMS - Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Fernando Remião
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Renata Silva
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
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Bernardo-Seisdedos G, Schedlbauer A, Pereira-Ortuzar T, Mato JM, Millet O. Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin. LIFE (BASEL, SWITZERLAND) 2023; 13:life13010222. [PMID: 36676171 PMCID: PMC9866752 DOI: 10.3390/life13010222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 01/14/2023]
Abstract
(1) Background: Human frataxin is an iron binding protein that participates in the biogenesis of iron sulfur clusters and enhances ferrochelatase activity. While frataxin association to other proteins has been extensively characterized up to the structural level, much less is known about the putative capacity of frataxin to interact with functionally related metabolites. In turn, current knowledge about frataxin's capacity to coordinate metal ions is limited to iron (II and III); (2) Methods: here, we used NMR spectroscopy, Molecular Dynamics, and Docking approaches to demonstrate new roles of frataxin; (3) Results: We demonstrate that frataxin also binds Zn2+ in a structurally similar way to Fe2+, but with lower affinity. In turn, both Fe2+-loaded and Zn2+-loaded frataxins specifically associate to protoporphyrin IX with micromolar affinity, while apo-frataxin does not bind to the porphyrin. Protoporphyrin IX association to metal-loaded frataxin shares the binding epitope with ferrochelatase; and (4) Conclusions: these findings expand the plethora of relevant molecular targets for frataxin and may help to elucidate the yet unknown different roles that this protein exerts in iron regulation and metabolism.
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Affiliation(s)
- Ganeko Bernardo-Seisdedos
- ATLAS Molecular Pharma, Bizkaia Science and Technology Park, 48160 Derio, Spain
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, 48160 Derio, Spain
| | - Andreas Schedlbauer
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, 48160 Derio, Spain
| | - Tania Pereira-Ortuzar
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, 48160 Derio, Spain
| | - José M. Mato
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, 48160 Derio, Spain
- Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Oscar Millet
- ATLAS Molecular Pharma, Bizkaia Science and Technology Park, 48160 Derio, Spain
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, 48160 Derio, Spain
- Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence:
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8
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Neuroinflammation in Friedreich's Ataxia. Int J Mol Sci 2022; 23:ijms23116297. [PMID: 35682973 PMCID: PMC9181348 DOI: 10.3390/ijms23116297] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 12/24/2022] Open
Abstract
Friedreich's ataxia (FRDA) is a rare genetic disorder caused by mutations in the gene frataxin, encoding for a mitochondrial protein involved in iron handling and in the biogenesis of iron-sulphur clusters, and leading to progressive nervous system damage. Although the overt manifestations of FRDA in the nervous system are mainly observed in the neurons, alterations in non-neuronal cells may also contribute to the pathogenesis of the disease, as recently suggested for other neurodegenerative disorders. In FRDA, the involvement of glial cells can be ascribed to direct effects caused by frataxin loss, eliciting different aberrant mechanisms. Iron accumulation, mitochondria dysfunction, and reactive species overproduction, mechanisms identified as etiopathogenic in neurons in FRDA, can similarly affect glial cells, leading them to assume phenotypes that can concur to and exacerbate neuron loss. Recent findings obtained in FRDA patients and cellular and animal models of the disease have suggested that neuroinflammation can accompany and contribute to the neuropathology. In this review article, we discuss evidence about the involvement of neuroinflammatory-related mechanisms in models of FRDA and provide clues for the modulation of glial-related mechanisms as a possible strategy to improve disease features.
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Cerebral Iron Deposition in Neurodegeneration. Biomolecules 2022; 12:biom12050714. [PMID: 35625641 PMCID: PMC9138489 DOI: 10.3390/biom12050714] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 02/04/2023] Open
Abstract
Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.
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10
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Deistung A, Jäschke D, Draganova R, Pfaffenrot V, Hulst T, Steiner KM, Thieme A, Giordano IA, Klockgether T, Tunc S, Münchau A, Minnerop M, Göricke SL, Reichenbach JR, Timmann D. Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias. Brain Commun 2022; 4:fcab306. [PMID: 35291442 PMCID: PMC8914888 DOI: 10.1093/braincomms/fcab306] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 10/28/2021] [Accepted: 01/05/2022] [Indexed: 11/13/2022] Open
Abstract
The cerebellar nuclei are a brain region with high iron content. Surprisingly,
little is known about iron content in the cerebellar nuclei and its possible
contribution to pathology in cerebellar ataxias, with the only exception of
Friedreich’s ataxia. In the present exploratory cross-sectional study,
quantitative susceptibility mapping was used to investigate volume, iron
concentration and total iron content of the dentate nuclei in common types of
hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with
spinocerebellar ataxias of types 1, 2, 3 and 6; 15 patients with
Friedreich’s ataxia; 18 patients with multiple system atrophy, cerebellar
type and 111 healthy controls were also included. All underwent 3 T MRI
and clinical assessments. For each specific ataxia subtype, voxel-based and
volumes-of-interest-based group analyses were performed in comparison with a
corresponding age- and sex-matched control group, both for volume, magnetic
susceptiblity (indicating iron concentration) and susceptibility mass
(indicating total iron content) of the dentate nuclei. Spinocerebellar ataxia of
type 1 and multiple system atrophy, cerebellar type patients showed higher
susceptibilities in large parts of the dentate nucleus but unaltered
susceptibility masses compared with controls. Friedreich’s ataxia
patients and, only on a trend level, spinocerebellar ataxia of type 2 patients
showed higher susceptibilities in more circumscribed parts of the dentate. In
contrast, spinocerebellar ataxia of type 6 patients revealed lower
susceptibilities and susceptibility masses compared with controls throughout the
dentate nucleus. Spinocerebellar ataxia of type 3 patients showed no significant
changes in susceptibility and susceptibility mass. Lower volume of the dentate
nuclei was found to varying degrees in all ataxia types. It was most pronounced
in spinocerebellar ataxia of type 6 patients and least prominent in
spinocerebellar ataxia of type 3 patients. The findings show that alterations in
susceptibility revealed by quantitative susceptibility mapping are common in the
dentate nuclei in different types of cerebellar ataxias. The most striking
changes in susceptibility were found in spinocerebellar ataxia of type 1,
multiple system atrophy, cerebellar type and spinocerebellar ataxia of type 6.
Because iron content is known to be high in glial cells but not in neurons of
the cerebellar nuclei, the higher susceptibility in spinocerebellar ataxia of
type 1 and multiple system atrophy, cerebellar type may be explained by a
reduction of neurons (increase in iron concentration) and/or an increase in
iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher
susceptibility and could also contribute. The lower susceptibility in SCA6
suggests a loss of iron-rich glial cells. Quantitative susceptibility maps
warrant future studies of iron content and iron-rich cells in ataxias to gain a
more comprehensive understanding of the pathogenesis of these diseases.
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Affiliation(s)
- Andreas Deistung
- University Clinic and Outpatient Clinic for Radiology, Department for Radiation Medicine, University Hospital Halle (Saale), Halle (Saale), Germany
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germany
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, Essen, Germany
| | - Dominik Jäschke
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, Essen, Germany
| | - Rossitza Draganova
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, Essen, Germany
| | - Viktor Pfaffenrot
- Erwin L. Hahn Institute for Magnetic Resonance Imaging, University Duisburg-Essen, Essen, Germany
| | - Thomas Hulst
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, Essen, Germany
- Erasmus University College, Erasmus School of Social and Behavioural Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Katharina M. Steiner
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, Essen, Germany
| | - Andreas Thieme
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, Essen, Germany
| | - Ilaria A. Giordano
- Department of Neurology, University Hospital Bonn, Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Thomas Klockgether
- Department of Neurology, University Hospital Bonn, Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Sinem Tunc
- Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany
- Department of Neurology, University of Lübeck, Lübeck, Germany
| | - Alexander Münchau
- Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany
| | - Martina Minnerop
- Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany
- Department of Neurology, Center for Movement Disorders and Neuromodulation, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Duesseldorf, Germany
| | - Sophia L. Göricke
- Institute of Diagnostic and Interventional Radiology and Neuroradiology, Essen University Hospital, Essen, Germany
| | - Jürgen R. Reichenbach
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germany
| | - Dagmar Timmann
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, Essen, Germany
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11
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Khan W, Corben LA, Bilal H, Vivash L, Delatycki MB, Egan GF, Harding IH. Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [ 18 F]-FEMPA PET Study. Mov Disord 2021; 37:218-224. [PMID: 34643298 DOI: 10.1002/mds.28825] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/08/2021] [Accepted: 09/21/2021] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Neuroinflammation is proposed to accompany, or even contribute to, neuropathology in Friedreich ataxia (FRDA), with implications for disease treatment and tracking. OBJECTIVES To examine brain glial activation and systemic immune dysfunction in people with FRDA and quantify their relationship with symptom severity, duration, and onset age. METHODS Fifteen individuals with FRDA and 13 healthy controls underwent brain positron emission tomography using the translocator protein (TSPO) radioligand [18 F]-FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines. RESULTS [18 F]-FEMPA binding was significantly increased in the dentate nuclei (d = 0.67), superior cerebellar peduncles (d = 0.74), and midbrain (d = 0.87), alongside increased plasma interleukin-6 (IL-6) (d = 0.73), in individuals with FRDA compared to controls. Increased [18 F]-FEMPA binding in the dentate nuclei, brainstem, and cerebellar anterior lobe correlated with earlier age of symptom onset (controlling for the genetic triplet repeat expansion length; all rpart < -0.6), and in the pons and anterior lobe with shorter disease duration (r = -0.66; -0.73). CONCLUSIONS Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness. © 2021 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Wasim Khan
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Louise A Corben
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.,Turner Institute for Brain and Mental Health and School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia
| | - Hiba Bilal
- Turner Institute for Brain and Mental Health and School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia
| | - Lucy Vivash
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.,Victorian Clinical Genetics Service, Melbourne, Victoria, Australia
| | - Gary F Egan
- Turner Institute for Brain and Mental Health and School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia.,Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia
| | - Ian H Harding
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia
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12
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Harding IH, Lynch DR, Koeppen AH, Pandolfo M. Central Nervous System Therapeutic Targets in Friedreich Ataxia. Hum Gene Ther 2021; 31:1226-1236. [PMID: 33238751 PMCID: PMC7757690 DOI: 10.1089/hum.2020.264] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Friedreich ataxia (FRDA) is an autosomal recessive inherited multisystem disease, characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate. In the current era of expanding therapeutic discovery in FRDA, including progress toward novel gene therapies, a deeper and more specific consideration of potential treatment targets in the nervous system is necessary. In this work, we have re-examined the neuropathology of FRDA, recognizing new issues superimposed on classical findings, and dissected the peripheral nervous system (PNS) and central nervous system (CNS) aspects of the disease and the affected cell types. Understanding the temporal course of neuropathological changes is needed to identify areas of modifiable disease progression and the CNS and PNS locations that can be targeted at different time points. As most major targets of long-term therapy are in the CNS, this review uses multiple tools for evaluation of the importance of specific CNS locations as targets. In addition to clinical observations, the conceptualizations in this study include physiological, pathological, and imaging approaches, and animal models. We believe that this review, through analysis of a more complete set of data derived from multiple techniques, provides a comprehensive summary of therapeutic targets in FRDA.
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Affiliation(s)
- Ian H Harding
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia.,Monash Biomedical Imaging, Monash University, Melbourne, Australia
| | - David R Lynch
- Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Arnulf H Koeppen
- Research, Neurology, and Pathology Services, Veterans Affairs Medical Center and Departments of Neurology and Pathology, Albany Medical College, Albany, New York, USA
| | - Massimo Pandolfo
- Laboratory of Experimental Neurology, Université Libre de Bruxelles (ULB), Brussels, Belgium
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13
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Gozt A, Hellewell S, Ward PGD, Bynevelt M, Fitzgerald M. Emerging Applications for Quantitative Susceptibility Mapping in the Detection of Traumatic Brain Injury Pathology. Neuroscience 2021; 467:218-236. [PMID: 34087394 DOI: 10.1016/j.neuroscience.2021.05.030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/16/2022]
Abstract
Traumatic brain injury (TBI) is a common but heterogeneous injury underpinned by numerous complex and interrelated pathophysiological mechanisms. An essential trace element, iron is abundant within the brain and involved in many fundamental neurobiological processes, including oxygen transportation, oxidative phosphorylation, myelin production and maintenance, as well as neurotransmitter synthesis and metabolism. Excessive levels of iron are neurotoxic and thus iron homeostasis is tightly regulated in the brain, however, many details about the mechanisms by which this is achieved are yet to be elucidated. A key mediator of oxidative stress, mitochondrial dysfunction and neuroinflammatory response, iron dysregulation is an important contributor to secondary injury in TBI. Advances in neuroimaging that leverage magnetic susceptibility properties have enabled increasingly comprehensive investigations into the distribution and behaviour of iron in the brain amongst healthy individuals as well as disease states such as TBI. Quantitative Susceptibility Mapping (QSM) is an advanced neuroimaging technique that promises quantitative estimation of local magnetic susceptibility at the voxel level. In this review, we provide an overview of brain iron and its homeostasis, describe recent advances enabling applications of QSM within the context of TBI and summarise the current state of the literature. Although limited, the emergent research suggests that QSM is a promising neuroimaging technique that can be used to investigate a host of pathophysiological changes that are associated with TBI.
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Affiliation(s)
- Aleksandra Gozt
- Curtin University, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Bentley, WA Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA Australia
| | - Sarah Hellewell
- Curtin University, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Bentley, WA Australia
| | - Phillip G D Ward
- Australian Research Council Centre of Excellence for Integrative Brain Function, VIC Australia; Turner Institute for Brain and Mental Health, Monash University, VIC Australia
| | - Michael Bynevelt
- Neurological Intervention and Imaging Service of Western Australia, Sir Charles Gairdner Hospital, Nedlands, WA Australia
| | - Melinda Fitzgerald
- Curtin University, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Bentley, WA Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA Australia.
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14
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Abstract
OBJECTIVE Friedreich's ataxia (FRDA) is the most common hereditary ataxia. It is a neurodegenerative disorder, characterized by progressive ataxia. FRDA is also associated with cognitive impairments. To date, the evolution of cognitive functioning is unknown. Our aim was to investigate the changes in the cognitive functioning of FRDA patients over an average eight-year timeframe. In addition, we aimed to study the relationship between cognitive changes and clinical variables. METHODS Twenty-nine FRDA patients who had been part of the sample of a previous study participated in the present study. The mean average time between the two assessments was 8.24 years. The participants completed an extensive battery of neuropsychological tests chosen to examine cognitive functioning in various cognitive domains: processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions and language. RESULTS At follow-up, cerebellar symptoms had worsened, and patients presented greater disability. Differences between baseline and follow-up were observed in motor and cognitive reaction times, several trials of the Stroop test, semantic fluency, and block designs. No other cognitive changes were observed. Deterioration in simple cognitive reactions times and block designs performance correlated with the progression of cerebellar symptoms. CONCLUSIONS Our study has demonstrated for the first time that patients with FRDA experience a significant decline over time in several cognitive domains. Specifically, after an eight-year period, FRDA patients worsened in processing speed, fluency, and visuoconstructive skills. This progression is unlikely to be due to greater motor or speech impairment.
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15
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Frataxins Emerge as New Players of the Intracellular Antioxidant Machinery. Antioxidants (Basel) 2021; 10:antiox10020315. [PMID: 33672495 PMCID: PMC7923443 DOI: 10.3390/antiox10020315] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/30/2022] Open
Abstract
Frataxin is a mitochondrial protein which deficiency causes Friedreich's ataxia, a cardio-neurodegenerative disease. The lack of frataxin induces the dysregulation of mitochondrial iron homeostasis and oxidative stress, which finally causes the neuronal death. The mechanism through which frataxin regulates the oxidative stress balance is rather complex and poorly understood. While the absence of human (Hfra) and yeast (Yfh1) frataxins turn out cells sensitive to oxidative stress, this does not occur when the frataxin gene is knocked-out in E. coli. To better understand the biological roles of Hfra and Yfh1 as endogenous antioxidants, we have studied their ability to inhibit the formation of reactive oxygen species (ROS) from Cu2+- and Fe3+-catalyzed degradation of ascorbic acid. Both proteins drastically reduce the formation of ROS, and during this process they are not oxidized. In addition, we have also demonstrated that merely the presence of Yfh1 or Hfra is enough to protect a highly oxidation-prone protein such as α-synuclein. This unspecific intervention (without a direct binding) suggests that frataxins could act as a shield to prevent the oxidation of a broad set of intracellular proteins, and reinforces that idea that frataxin can be used to prevent neurological pathologies linked to an enhanced oxidative stress.
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16
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Dales JP, Desplat-Jégo S. Metal Imbalance in Neurodegenerative Diseases with a Specific Concern to the Brain of Multiple Sclerosis Patients. Int J Mol Sci 2020; 21:E9105. [PMID: 33266021 PMCID: PMC7730295 DOI: 10.3390/ijms21239105] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/29/2020] [Accepted: 11/19/2020] [Indexed: 12/16/2022] Open
Abstract
There is increasing evidence that deregulation of metals contributes to a vast range of neurodegenerative diseases including multiple sclerosis (MS). MS is a chronic inflammatory disease of the central nervous system (CNS) manifesting disability and neurological symptoms. The precise origin of MS is unknown, but the disease is characterized by focal inflammatory lesions in the CNS associated with an autoimmune reaction against myelin. The treatment of this disease has mainly been based on the prescription of immunosuppressive and immune-modulating agents. However, the rate of progressive disability and early mortality is still worrisome. Metals may represent new diagnostic and predictive markers of severity and disability as well as innovative candidate drug targets for future therapies. In this review, we describe the recent advances in our understanding on the role of metals in brain disorders of neurodegenerative diseases and MS patients.
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Affiliation(s)
- Jean-Philippe Dales
- Institute of Neurophysiopathology, CNRS, INP, Aix-Marseille University, 13005 Marseille, France;
- Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Pavillon Etoile, Pôle de Biologie, Service d’anatomie-pathologie, CEDEX 20, 13915 Marseille, France
| | - Sophie Desplat-Jégo
- Institute of Neurophysiopathology, CNRS, INP, Aix-Marseille University, 13005 Marseille, France;
- Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, Pôle de Biologie, Service d’Immunologie, 13005 Marseille, France
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17
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Zhang YC, Wan GJ, Wang WH, Li Y, Yu Y, Zhang YX, Chen FJ, Pan WD. Enhancement of the geomagnetic field reduces the phototaxis of rice brown planthopper Nilaparvata lugens associated with frataxin down-regulation. INSECT SCIENCE 2020; 27:1043-1052. [PMID: 31389658 DOI: 10.1111/1744-7917.12714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 07/18/2019] [Accepted: 07/22/2019] [Indexed: 06/10/2023]
Abstract
The geomagnetic field (GMF) is an environmental cue that provides directional information for animals. The intensity of GMF is varied over space and time. Variations in the GMF intensity affect the navigation of animals and their physiology. In this study, the phototaxis of the migratory insect rice planthopper Nilaparvata lugens (N. lugens) and frataxin in N. lugens (Nl-fh), which is a mitochondrial protein required for cellular iron homeostasis and iron-sulfur cluster assembly, were investigated by using different intensities of magnetic field. From the results, individuals of N. lugens showed decreased phototaxis when reared and tested in a behavioral arena under a strong magnetic field. Besides the reduction in performance, an accompanying effect of the strong magnetic field condition was a reduced level of Nl-fh-messenger RNA, and a Nl-fh knockdown indeed impaired the phototactic behavior in a tested sample of insects. This leads to the conclusion that the expression of frataxin is dependent on the strength of the surrounding magnetic field and that functional frataxin facilitates phototactic behavior in N. lugens.
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Affiliation(s)
- Ying-Chao Zhang
- Beijing Key Laboratory of Bioelectromagnetics, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Gui-Jun Wan
- Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing, China
| | - Wei-Hong Wang
- Beijing Key Laboratory of Bioelectromagnetics, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yue Li
- Beijing Key Laboratory of Bioelectromagnetics, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, China
| | - Yang Yu
- Beijing Key Laboratory of Bioelectromagnetics, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, China
| | - Yu-Xia Zhang
- Beijing Key Laboratory of Bioelectromagnetics, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, China
| | - Fa-Jun Chen
- Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing, China
| | - Wei-Dong Pan
- Beijing Key Laboratory of Bioelectromagnetics, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, China
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18
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Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion? Antioxidants (Basel) 2020; 9:E664. [PMID: 32722309 PMCID: PMC7465446 DOI: 10.3390/antiox9080664] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/17/2020] [Accepted: 07/19/2020] [Indexed: 12/12/2022] Open
Abstract
Friedreich´s ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those "antioxidant" drugs that went beyond the disease´s models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials.
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Affiliation(s)
- Laura R. Rodríguez
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
| | - Tamara Lapeña
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - Pablo Calap-Quintana
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - María Dolores Moltó
- Department of Genetics, Universitat de València-INCLIVA, 46100 Valencia, Spain;
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 46100 Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
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19
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Kim Y, Connor JR. The roles of iron and HFE genotype in neurological diseases. Mol Aspects Med 2020; 75:100867. [PMID: 32654761 DOI: 10.1016/j.mam.2020.100867] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/21/2020] [Accepted: 05/24/2020] [Indexed: 12/13/2022]
Abstract
Iron accumulation is a recurring pathological phenomenon in many neurological diseases including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and others. Iron is essential for normal development and functions of the brain; however, excess redox-active iron can also lead to oxidative damage and cell death. Especially for terminally differentiated cells like neurons, regulation of reactive oxygen species is critical for cell viability. As a result, cellular iron level is tightly regulated. Although iron accumulation related to neurological diseases has been well documented, the pathoetiological contributions of the homeostatic iron regulator (HFE), which controls cellular iron uptake, is less understood. Furthermore, a common HFE variant, H63D HFE, has been identified as a modifier of multiple neurological diseases. This review will discuss the roles of iron and HFE in the brain as well as their impact on various disease processes.
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Affiliation(s)
- Yunsung Kim
- Penn State College of Medicine, Department of Neurosurgery, Hershey, PA, USA
| | - James R Connor
- Penn State College of Medicine, Department of Neurosurgery, Hershey, PA, USA.
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20
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Rasschaert M, Weller RO, Schroeder JA, Brochhausen C, Idée JM. Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review. J Magn Reson Imaging 2020; 52:1293-1305. [PMID: 32246802 PMCID: PMC7687192 DOI: 10.1002/jmri.27124] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/21/2022] Open
Abstract
The unexpected appearance of T1 hyperintensities, mostly in the dentate nucleus and the globus pallidus, during nonenhanced MRI was reported in 2014. This effect is associated with prior repeated administrations of gadolinium (Gd)‐based contrast agents (GBCAs) in patients with a functional blood–brain barrier (BBB). It is widely assumed that GBCAs do not cross the intact BBB, but the observation of these hypersignals raises questions regarding this assumption. This review critically discusses the mechanisms of Gd accumulation in the brain with regard to access pathways, Gd species, tissue distribution, and subcellular location. We propose the hypothesis that there is early access of Gd species to cerebrospinal fluid, followed by passive diffusion into the brain parenchyma close to the cerebral ventricles. When accessing areas rich in endogenous metals or phosphorus, the less kinetically stable GBCAs would dissociate, and Gd would bind to endogenous macromolecules, and/or precipitate within the brain tissue. It is also proposed that Gd species enter the brain parenchyma along penetrating cortical arteries in periarterial pial‐glial basement membranes and leave the brain along intramural peri‐arterial drainage (IPAD) pathways. Lastly, Gd/GBCAs may access the brain parenchyma directly from the blood through the BBB in the walls of capillaries. It is crucial to distinguish between the physiological distribution and drainage pathways for GBCAs and the possible dissociation of less thermodynamically/kinetically stable GBCAs that lead to long‐term Gd deposition in the brain. Level of Evidence 5. Technical Efficacy Stage 3.
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Affiliation(s)
| | - Roy O Weller
- Neuropathology, Faculty of Medicine University of Southampton, Southampton General Hospital, Southampton, UK
| | - Josef A Schroeder
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | | | - Jean-Marc Idée
- Guerbet, Research and Innovation Division, Aulnay-sous-Bois, France
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21
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De Samber B, Vanden Berghe T, Meul E, Bauters S, Seyrich M, Smet J, De Paepe B, da Silva JC, Bohic S, Cloetens P, Van Coster R, Vandenabeele P, Vincze L. Nanoscopic X-ray imaging and quantification of the iron cellular architecture within single fibroblasts of Friedreich's ataxia patients. JOURNAL OF SYNCHROTRON RADIATION 2020; 27:185-198. [PMID: 31868751 DOI: 10.1107/s1600577519015510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 11/17/2019] [Indexed: 06/10/2023]
Abstract
Friedreich's ataxia (FRDA) is a neurodegenerative disease characterized by an increase in intracytoplasmic iron concentration. Here the nanoscale iron distribution within single fibroblasts from FRDA patients was investigated using synchrotron-radiation-based nanoscopic X-ray fluorescence and X-ray in-line holography at the ID16A nano-imaging beamline of the ESRF. This unique probe was deployed to uncover the iron cellular two-dimensional architecture of freeze-dried FRDA fibroblasts. An unsurpassed absolute detection capability of 180 iron atoms within a 30 nm × 50 nm nanoscopic X-ray beam footprint was obtained using state-of-the-art X-ray focusing optics and a large-solid-angle detection system. Various micrometre-sized iron-rich organelles could be revealed for the first time, tentatively identified as endoplasmic reticulum, mitochondria and lysosomes. Also a multitude of nanoscopic iron hot-spots were observed in the cytosol, interpreted as chaperoned iron within the fibroblast's labile iron pool. These observations enable new hypotheses on the storage and trafficking of iron in the cell and ultimately to a better understanding of iron-storage diseases such as Friedreich's ataxia.
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Affiliation(s)
- Björn De Samber
- Department of Analytical Chemistry, Ghent University, Ghent, Belgium
| | | | - Eline Meul
- VIB Center for Inflammation Research, Ghent, Belgium
| | | | | | - Joél Smet
- Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
| | - Boel De Paepe
- Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
| | | | | | | | - Rudy Van Coster
- Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
| | | | - Laszlo Vincze
- Department of Analytical Chemistry, Ghent University, Ghent, Belgium
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22
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Pattern of Cerebellar Atrophy in Friedreich's Ataxia-Using the SUIT Template. THE CEREBELLUM 2019; 18:435-447. [PMID: 30771164 DOI: 10.1007/s12311-019-1008-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich's ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich's ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls. We demonstrate that the cerebellar volume in FRDA is generally not significantly different from healthy controls but mild lobular atrophy develops beyond normal aging. The medial parts of lobule VI, housing the somatotopic representation of tongue and lips, are the major site of this lobular atrophy, which possibly reflects speech impairment. Extended white matter affection correlates with disease severity across and beyond the cerebellar inflow and outflow tracts. The dentate nucleus, as a major site of cerebellar degeneration, shows a mean volume loss of about 30%. Remarkably, not the atrophy but the T2 signal decrease of the dentate nuclei highly correlates with disease duration and severity.
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23
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Boesch S, Indelicato E. Erythropoietin and Friedreich Ataxia: Time for a Reappraisal? Front Neurosci 2019; 13:386. [PMID: 31105516 PMCID: PMC6491891 DOI: 10.3389/fnins.2019.00386] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 04/04/2019] [Indexed: 12/24/2022] Open
Abstract
Friedreich ataxia (FRDA) is a rare neurological disorder due to deficiency of the mitochondrial protein frataxin. Frataxin deficiency results in impaired mitochondrial function and iron deposition in affected tissues. Erythropoietin (EPO) is a cytokine which was mostly known as a key regulator of erythropoiesis until cumulative evidence showed additional neurotrophic and neuroprotective properties. These features offered the rationale for advancement of EPO in clinical trials in different neurological disorders in the past years, including FRDA. Several mechanisms of action of EPO may be beneficial in FRDA. First of all, EPO exposure results in frataxin upregulation in vitro and in vivo. By promoting erythropoiesis, EPO influences iron metabolism and induces shifts in iron pool which may ameliorate conditions of free iron excess and iron accumulation. Furthermore, EPO signaling is crucial for mitochondrial gene activation and mitochondrial biogenesis. Up to date nine clinical trials investigated the effects of EPO and derivatives in FRDA. The majority of these studies had a proof-of-concept design. Considering the natural history of FRDA, all of them were too short in duration and not powered for clinical changes. However, these studies addressed significant issues in the treatment with EPO, such as (1) the challenge of the dose finding, (2) stability of frataxin up-regulation, (3) continuous versus intermittent stimulation with EPO/regimen, or (4) tissue changes after EPO exposure in humans in vivo (muscle biopsy, brain imaging). Despite several clinical trials in the past, no treatment is available for the treatment of FRDA. Current lines of research focus on gene therapy, frataxin replacement strategies and on regulation of key metabolic checkpoints such as NrF2. Due to potential crosstalk with all these mechanisms, interventions on the EPO pathway still represent a valuable research field. The recent development of small EPO mimetics which maintain cytoprotective properties without erythropoietic action may open a new era in EPO research for the treatment of FRDA.
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Affiliation(s)
- Sylvia Boesch
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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24
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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: 57] [Impact Index Per Article: 9.5] [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.
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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
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25
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Ward PGD, Harding IH, Close TG, Corben LA, Delatycki MB, Storey E, Georgiou-Karistianis N, Egan GF. Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia. Mov Disord 2019; 34:335-343. [PMID: 30624809 DOI: 10.1002/mds.27606] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/26/2018] [Accepted: 12/06/2018] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Friedreich ataxia is a recessively inherited, progressive neurological disease characterized by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of abnormalities in these structures. METHODS Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n = 20) and healthy controls (n = 18) over a 2-year period. RESULTS The longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Specifically, atrophy was maximal in individuals early in the disease course, whereas the rate of iron concentration increased with disease progression. CONCLUSIONS Progressive dentate nucleus abnormalities are evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a 2-year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool. © 2019 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Phillip G D Ward
- Monash Biomedical Imaging, Monash University, Melbourne, Australia.,School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia.,Australian Research Council Centre of Excellence for Integrative Brain Function, Melbourne, Australia
| | - Ian H Harding
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia
| | - Thomas G Close
- Monash Biomedical Imaging, Monash University, Melbourne, Australia
| | - Louise A Corben
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia.,Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Parkville, Australia
| | - Martin B Delatycki
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia.,Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Parkville, Australia.,Victorian Clinical Genetics Service, Parkville, Australia
| | - Elsdon Storey
- Department of Medicine, Monash University, Melbourne, Australia
| | - Nellie Georgiou-Karistianis
- School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia
| | - Gary F Egan
- Monash Biomedical Imaging, Monash University, Melbourne, Australia.,School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia.,Australian Research Council Centre of Excellence for Integrative Brain Function, Melbourne, Australia
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26
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Abstract
Friedreich's ataxia (FRDA) is a degenerative disease that affects both the central and the peripheral nervous systems and non-neural tissues including, mainly, heart, and endocrine pancreas. It is an autosomal recessive disease caused by a GAA triplet-repeat localized within an Alu sequence element in intron 1 of frataxin (FXN) gene, which encodes a mitochondrial protein FXN. This protein is essential for mitochondrial function by the involvement of iron-sulfur cluster biogenesis. The effects of its deficiency also include disruption of cellular, particularly mitochondrial, iron homeostasis, i.e., relatively more iron accumulated in mitochondria and less iron presented in cytosol. Though iron toxicity is commonly thought to be mediated via Fenton reaction, oxidative stress seems not to be the main problem to result in detrimental effects on cell survival, particularly neuron survival. Therefore, the basic research on FXN function is urgently demanded to understand the disease. This chapter focuses on the outcome of FXN expression, regulation, and function in cellular or animal models of FRDA and on iron pathophysiology in the affected tissues. Finally, therapeutic strategies based on the control of iron toxicity and iron cellular redistribution are considered. The combination of multiple therapeutic targets including iron, oxidative stress, mitochondrial function, and FXN regulation is also proposed.
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Affiliation(s)
- Kuanyu Li
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China.
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27
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A new MRI marker of ataxia with oculomotor apraxia. Eur J Radiol 2018; 110:187-192. [PMID: 30599859 DOI: 10.1016/j.ejrad.2018.11.035] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 11/23/2018] [Accepted: 11/28/2018] [Indexed: 12/18/2022]
Abstract
PURPOSE Evaluate the specificity and sensitivity of disappearance of susceptibility weighted imaging (SWI) dentate nuclei (DN) hypointensity in oculomotor apraxia patients (AOA). METHOD In this prospective study, 27 patients with autosomal genetic ataxia (AOA (n = 11), Friedreich ataxia and ataxia with vitamin E deficit (n = 4), and dominant genetic ataxia (n = 12)) were included along with fifteen healthy controls. MRIs were qualitatively classified for the presence or absence of DN hypointensity on FLAIR and SWI sequences. The MRIs were then quantitatively studied, with measurement of a ratio of DN over brainstem white matter signal intensity through manual delineation. The institutional review board approved this study, and written informed consent was obtained. In the cross-sectional analysis, the Mann-Whitney test was applied. RESULTS Qualitatively, the eleven AOA patients presented absence of both DN SWI and FLAIR hyposignals; three dominant genetic ataxia patients had moderate SWI DN hyposignal and absent FLAIR hyposignal; the thirteen remaining subjects presented normal SWI and FLAIR DN hyposignal. Absence of DN SWI hypointensity was 100% sensitive and specific to AOA. Quantitative signal intensity ratio (mean ± standard deviation) of the AOA group (98·96 ± 5·37%) was significantly higher than in control subjects group (76.40 ± 8.34%; p < 0.001), dominant genetic ataxia group (81·15 ± 9·94%; p < 0·001), and Friedreich ataxia and ataxia with vitamin E deficit group (87·56 ± 2·78%; p < 0·02). CONCLUSION This small study shows that loss of the normal hypointensity in the dentate nucleus on both SWI and FLAIR imaging at 3 T is a highly sensitive and specific biomarker for AOA.
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28
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Abstract
The dentate nucleus (DN) of the cerebellum is the major output nucleus of the cerebellum and is rich in iron. Quantitative susceptibility mapping (QSM) provides better iron-sensitive MRI contrast to delineate the boundary of the DN than either T2-weighted images or susceptibility-weighted images. Prior DN atlases used T2-weighted or susceptibility-weighted images to create DN atlases. Here, we employ QSM images to develop an improved dentate nucleus atlas for use in imaging studies. The DN was segmented in QSM images from 38 healthy volunteers. The resulting DN masks were transformed to a common space and averaged to generate the DN atlas. The center of mass of the left and right sides of the QSM-based DN atlas in the Montreal Neurological Institute space was -13.8, -55.8, and -36.4 mm, and 13.8, -55.7, and -36.4 mm, respectively. The maximal probability and mean probability of the DN atlas with the individually segmented DNs in this cohort were 100 and 39.3%, respectively, in contrast to the maximum probability of approximately 75% and the mean probability of 23.4 to 33.7% with earlier DN atlases. Using QSM, which provides superior iron-sensitive MRI contrast for delineating iron-rich structures, an improved atlas for the dentate nucleus has been generated. The atlas can be applied to investigate the role of the DN in both normal cortico-cerebellar physiology and the variety of disease states in which it is implicated.
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29
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Napierala JS, Li Y, Lu Y, Lin K, Hauser LA, Lynch DR, Napierala M. Comprehensive analysis of gene expression patterns in Friedreich's ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers. Dis Model Mech 2018; 10:1353-1369. [PMID: 29125828 PMCID: PMC5719256 DOI: 10.1242/dmm.030536] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/21/2017] [Indexed: 12/30/2022] Open
Abstract
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease usually caused by large homozygous expansions of GAA repeat sequences in intron 1 of the frataxin (FXN) gene. FRDA patients homozygous for GAA expansions have low FXN mRNA and protein levels when compared with heterozygous carriers or healthy controls. Frataxin is a mitochondrial protein involved in iron–sulfur cluster synthesis, and many FRDA phenotypes result from deficiencies in cellular metabolism due to lowered expression of FXN. Presently, there is no effective treatment for FRDA, and biomarkers to measure therapeutic trial outcomes and/or to gauge disease progression are lacking. Peripheral tissues, including blood cells, buccal cells and skin fibroblasts, can readily be isolated from FRDA patients and used to define molecular hallmarks of disease pathogenesis. For instance, FXN mRNA and protein levels as well as FXN GAA-repeat tract lengths are routinely determined using all of these cell types. However, because these tissues are not directly involved in disease pathogenesis, their relevance as models of the molecular aspects of the disease is yet to be decided. Herein, we conducted unbiased RNA sequencing to profile the transcriptomes of fibroblast cell lines derived from 18 FRDA patients and 17 unaffected control individuals. Bioinformatic analyses revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins in FRDA fibroblasts. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in FRDA fibroblasts. Finally, comparison of genes differentially expressed in FRDA fibroblasts to three previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease. When performed on statistically meaningful sample group sizes, unbiased global profiling analyses utilizing peripheral tissues are critical for the discovery and validation of FRDA disease biomarkers. Summary: Transcriptome profiling of Friedreich's ataxia fibroblasts by RNA sequencing reveals that this peripheral tissue can be used as a disease model for gene expression biomarker discovery.
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Affiliation(s)
- Jill Sergesketter Napierala
- University of Alabama at Birmingham, Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, 1825 University Blvd., Birmingham, Alabama 35294, USA
| | - Yanjie Li
- University of Alabama at Birmingham, Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, 1825 University Blvd., Birmingham, Alabama 35294, USA
| | - Yue Lu
- University of Texas MD Anderson Cancer Center, Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, Science Park, Smithville, Texas 78957, USA
| | - Kevin Lin
- University of Texas MD Anderson Cancer Center, Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, Science Park, Smithville, Texas 78957, USA
| | - Lauren A Hauser
- Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia, Abramson Research Center Room 502, Philadelphia, PA 19104, USA
| | - David R Lynch
- Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia, Abramson Research Center Room 502, Philadelphia, PA 19104, USA
| | - Marek Napierala
- University of Alabama at Birmingham, Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, 1825 University Blvd., Birmingham, Alabama 35294, USA .,Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, 61-704, Poland
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30
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Monnier V, Llorens JV, Navarro JA. Impact of Drosophila Models in the Study and Treatment of Friedreich's Ataxia. Int J Mol Sci 2018; 19:E1989. [PMID: 29986523 PMCID: PMC6073496 DOI: 10.3390/ijms19071989] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/26/2018] [Accepted: 07/03/2018] [Indexed: 02/07/2023] Open
Abstract
Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models.
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Affiliation(s)
- Véronique Monnier
- Unité de Biologie Fonctionnelle et Adaptative (BFA), Sorbonne Paris Cité, Université Paris Diderot, UMR8251 CNRS, 75013 Paris, France.
| | - Jose Vicente Llorens
- Department of Genetics, University of Valencia, Campus of Burjassot, 96100 Valencia, Spain.
| | - Juan Antonio Navarro
- Lehrstuhl für Entwicklungsbiologie, Universität Regensburg, 93040 Regensburg, Germany.
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31
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Chiang S, Kalinowski DS, Jansson PJ, Richardson DR, Huang MLH. Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich's ataxia. Neurochem Int 2018; 117:35-48. [PMID: 28782591 DOI: 10.1016/j.neuint.2017.08.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 07/25/2017] [Accepted: 08/03/2017] [Indexed: 01/09/2023]
Abstract
Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson's, Alzheimer's and Huntington's disease. Friedreich's ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism. Dys-regulation of iron metabolism in these compartments, results in the accumulation of inorganic iron deposits in the mitochondrial matrix that is thought to potentiate oxidative damage observed in FA. Therefore, the maintenance of mitochondrial homeostasis is crucial in the progression of neuro-degenerative conditions, particularly in FA. In this review, vital mitochondrial homeostatic processes and their roles in FA pathogenesis will be discussed. These include mitochondrial iron processing, mitochondrial dynamics (fusion and fission processes), mitophagy, mitochondrial biogenesis, mitochondrial energy production and calcium metabolism.
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Affiliation(s)
- Shannon Chiang
- Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Danuta S Kalinowski
- Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Patric J Jansson
- Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Des R Richardson
- Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia.
| | - Michael L-H Huang
- Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia.
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32
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Calap-Quintana P, Navarro JA, González-Fernández J, Martínez-Sebastián MJ, Moltó MD, Llorens JV. Drosophila melanogaster Models of Friedreich's Ataxia. BIOMED RESEARCH INTERNATIONAL 2018; 2018:5065190. [PMID: 29850527 PMCID: PMC5907503 DOI: 10.1155/2018/5065190] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 01/29/2018] [Accepted: 02/28/2018] [Indexed: 11/17/2022]
Abstract
Friedreich's ataxia (FRDA) is a rare inherited recessive disorder affecting the central and peripheral nervous systems and other extraneural organs such as the heart and pancreas. This incapacitating condition usually manifests in childhood or adolescence, exhibits an irreversible progression that confines the patient to a wheelchair, and leads to early death. FRDA is caused by a reduced level of the nuclear-encoded mitochondrial protein frataxin due to an abnormal GAA triplet repeat expansion in the first intron of the human FXN gene. FXN is evolutionarily conserved, with orthologs in essentially all eukaryotes and some prokaryotes, leading to the development of experimental models of this disease in different organisms. These FRDA models have contributed substantially to our current knowledge of frataxin function and the pathogenesis of the disease, as well as to explorations of suitable treatments. Drosophila melanogaster, an organism that is easy to manipulate genetically, has also become important in FRDA research. This review describes the substantial contribution of Drosophila to FRDA research since the characterization of the fly frataxin ortholog more than 15 years ago. Fly models have provided a comprehensive characterization of the defects associated with frataxin deficiency and have revealed genetic modifiers of disease phenotypes. In addition, these models are now being used in the search for potential therapeutic compounds for the treatment of this severe and still incurable disease.
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Affiliation(s)
- P. Calap-Quintana
- Department of Genetics, University of Valencia, Campus of Burjassot, Valencia, Spain
| | - J. A. Navarro
- Institute of Zoology, University of Regensburg, Regensburg, Germany
| | - J. González-Fernández
- Department of Genetics, University of Valencia, Campus of Burjassot, Valencia, Spain
- Biomedical Research Institute INCLIVA, Valencia, Spain
| | | | - M. D. Moltó
- Department of Genetics, University of Valencia, Campus of Burjassot, Valencia, Spain
- Biomedical Research Institute INCLIVA, Valencia, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - J. V. Llorens
- Department of Genetics, University of Valencia, Campus of Burjassot, Valencia, Spain
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Sánchez M, Palacios Ò, Buchensky C, Sabio L, Gomez-Casati DF, Pagani MA, Capdevila M, Atrian S, Dominguez-Vera JM. Copper redox chemistry of plant frataxins. J Inorg Biochem 2018; 180:135-140. [PMID: 29277024 DOI: 10.1016/j.jinorgbio.2017.11.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Revised: 11/22/2017] [Accepted: 11/24/2017] [Indexed: 01/15/2023]
Abstract
The presence of a conserved cysteine residue in the C-terminal amino acid sequences of plant frataxins differentiates these frataxins from those of other kingdoms and may be key in frataxin assembly and function. We report a full study on the ability of Arabidopsis (AtFH) and Zea mays (ZmFH-1 and ZmFH-2) frataxins to assemble into disulfide-bridged dimers by copper-driven oxidation and to revert to monomers by chemical reduction. We monitored the redox assembly-disassembly process by electrospray ionization mass spectrometry, electrophoresis, UV-Vis spectroscopy, and fluorescence measurements. We conclude that plant frataxins AtFH, ZmFH-1 and ZmFH-2 are oxidized by Cu2+ and exhibit redox cysteine monomer - cystine dimer interexchange. Interestingly, the tendency to interconvert is not the same for each protein. Through yeast phenotypic rescue experiments, we show that plant frataxins are important for plant survival under conditions of excess copper, indicating that these proteins might be involved in copper metabolism.
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Affiliation(s)
- Manu Sánchez
- Departamento de Química Inorgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, 18071 Granada, Spain
| | - Òscar Palacios
- Departament de Química, Facultat de Ciències, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain
| | - Celeste Buchensky
- Centro de Estudios Fotosintéticos y Bioquímicos, Universidad Nacional de Rosario, CONICET, 2000 Rosario, Argentina
| | - Laura Sabio
- Departamento de Química Inorgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, 18071 Granada, Spain
| | - Diego Fabian Gomez-Casati
- Centro de Estudios Fotosintéticos y Bioquímicos, Universidad Nacional de Rosario, CONICET, 2000 Rosario, Argentina
| | - Maria Ayelen Pagani
- Centro de Estudios Fotosintéticos y Bioquímicos, Universidad Nacional de Rosario, CONICET, 2000 Rosario, Argentina
| | - Mercè Capdevila
- Departament de Química, Facultat de Ciències, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
| | - Silvia Atrian
- Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain
| | - Jose M Dominguez-Vera
- Departamento de Química Inorgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, 18071 Granada, Spain.
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Vela D. Hepcidin, an emerging and important player in brain iron homeostasis. J Transl Med 2018; 16:25. [PMID: 29415739 PMCID: PMC5803919 DOI: 10.1186/s12967-018-1399-5] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 01/31/2018] [Indexed: 02/08/2023] Open
Abstract
Hepcidin is emerging as a new important factor in brain iron homeostasis. Studies suggest that there are two sources of hepcidin in the brain; one is local and the other comes from the circulation. Little is known about the molecular mediators of local hepcidin expression, but inflammation and iron-load have been shown to induce hepcidin expression in the brain. The most important source of hepcidin in the brain are glial cells. Role of hepcidin in brain functions has been observed during neuronal iron-load and brain hemorrhage, where secretion of abundant hepcidin is related with the severity of brain damage. This damage can be reversed by blocking systemic and local hepcidin secretion. Studies have yet to unveil its role in other brain conditions, but the rationale exists, since these conditions are characterized by overexpression of the factors that stimulate brain hepcidin expression, such as inflammation, hypoxia and iron-overload.
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Affiliation(s)
- Driton Vela
- Department of Physiology, Faculty of Medicine, University of Prishtina, Martyr's Boulevard n.n., 10000, Prishtina, Kosova.
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Nanoscopic X-ray fluorescence imaging and quantification of intracellular key-elements in cryofrozen Friedreich's ataxia fibroblasts. PLoS One 2018; 13:e0190495. [PMID: 29342155 PMCID: PMC5771581 DOI: 10.1371/journal.pone.0190495] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 12/13/2017] [Indexed: 11/19/2022] Open
Abstract
Synchrotron radiation based nanoscopic X-ray fluorescence (SR nano-XRF) analysis can visualize trace level elemental distribution in a fully quantitative manner within single cells. However, in-air XRF analysis requires chemical fixation modifying the cell's chemical composition. Here, we describe first nanoscopic XRF analysis upon cryogenically frozen (-150°C) fibroblasts at the ID16A-NI 'Nano-imaging' end-station located at the European Synchrotron Radiation Facility (ESRF) in Grenoble (France). Fibroblast cells were obtained from skin biopsies from control and Friedreich's ataxia (FRDA) patients. FRDA is an autosomal recessive disorder with dysregulation of iron metabolism as a key feature. By means of the X-ray Fundamental Parameter (FP) method, including absorption correction of the ice layer deposited onto the fibroblasts, background-corrected mass fraction elemental maps of P, S, Cl, K, Ca, Fe and Zn of entire cryofrozen human fibroblasts were obtained. Despite the presence of diffracting microcrystals in the vitreous ice matrix and minor sample radiation damage effects, clusters of iron-rich hot-spots with similar mass fractions were found in the cytoplasm of both control and FRDA fibroblasts. Interestingly, no significant difference in the mean iron concentration was found in the cytoplasm of FRDA fibroblasts, but a significant decrease in zinc concentration. This finding might underscore metal dysregulation, beyond iron, in cells derived from FRDA patients. In conclusion, although currently having slightly increased limits of detection (LODs) compared to non-cryogenic mode, SR based nanoscopic XRF under cryogenic sample conditions largely obliterates the debate on chemical sample preservation and provides a unique tool for trace level elemental imaging in single cells close to their native state with a superior spatial resolution of 20 nm.
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Abstract
This chapter summarizes the neuropathologic features of nonneoplastic disorders of the adult cerebellum. Gait ataxia and extremity dysmetria are clinical manifestations of diseases that interrupt the complex cerebellar circuitry between the neurons of the cerebellar cortex, the cerebellar nuclei (especially the dentate nuclei), and the inferior olivary nuclei. The cerebellum is a prominent target of several sporadic and hereditary neurodegenerative diseases, including multiple system atrophy, spinocerebellar ataxia, and Friedreich ataxia. Purkinje cells display selective vulnerability to hypoxia but a surprising resistance to hypoglycemia. A classic toxin that damages the cerebellar cortex is methylmercury, but the most common injurious agent to Purkinje cells is ethanol. Many drugs cause ataxia, but doubts continue about phenytoin. Ischemic lesions of the cerebellum due to arterial thrombosis or embolism cause a spectrum of symptoms and signs, depending on the territory involved. Large hemorrhages have an unfavorable prognosis because they displace critical brainstem structures or penetrate into the fourth ventricle. Fungal infections and toxoplasmosis of the cerebellum, and cerebellar progressive multifocal leukoencephalopathy, have become rarer because of improved control of the acquired immunodeficiency syndrome. Ataxia is a prominent feature of prion disease. Adult-onset Niemann-Pick type C1 disease and Kufs disease may have a predominantly ataxic clinical phenotype. The adult cerebellum is also vulnerable to several leukodystrophies. A rare but widely recognized complication of cancer is paraneoplastic cerebellar degeneration.
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Affiliation(s)
- Arnulf H Koeppen
- Research, Neurology, and Pathology Services, Veterans Affairs Medical Center and Departments of Neurology and Pathology, Albany Medical College, Albany, NY, United States.
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Fingerhut S, Niehoff AC, Sperling M, Jeibmann A, Paulus W, Niederstadt T, Allkemper T, Heindel W, Holling M, Karst U. Spatially resolved quantification of gadolinium deposited in the brain of a patient treated with gadolinium-based contrast agents. J Trace Elem Med Biol 2018; 45:125-130. [PMID: 29173468 DOI: 10.1016/j.jtemb.2017.10.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 10/11/2017] [Indexed: 01/19/2023]
Abstract
Due to its paramagnetic properties resulting from seven unpaired f-electrons, Gd is frequently applied in magnetic resonance imaging examinations. Due to the acute toxicity of free Gd3+, ligand ions based on polyaminocarboxylic acids are used to create thermodynamically stable linear or macrocyclic complexes. The highly water soluble Gd-based contrast agents (GBCAs) are known to be excreted fast and unmetabolized, mostly via the kidneys. Nevertheless, recent studies showed that Gd traces persists not only in animal but also in human brain. Aim of this study was the development and application of an analytical method for the spatially resolved quantification of gadolinium traces in human brain thin sections of a patient treated with GBCAs. For this retrospective study different human brain regions were selected to analyze the distribution of gadolinium. An additional patient served as control sample, as no GBCA was administered. Deep-frozen brain thin sections were analyzed by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and matrix-matched gelatin standards were prepared to quantify the gadolinium deposits via an external calibration. LA-ICP-MS analyses with high spatial resolution showed gadolinium deposits in different brain regions with highest concentrations above 800ngg-1 more than two years after the last application of a GBCA. An excellent limit of quantification of 7ngg-1, which is far below the limits of detection of MRI methods, could be achieved. The found concentrations confirm recent reports on gadolinium depositions in human brain, which were obtained without high spatial resolution. LA-ICP-MS provides limits of quantification, which are well suited to detect ultratrace amounts of gadolinium in human brain. Therefore, it provides valuable information on the distribution of gadolinium traces in the human brain even after single administration of GBCAs.
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Affiliation(s)
- Stefanie Fingerhut
- Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 30, 48149 Münster, Germany
| | - Ann-Christin Niehoff
- Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 30, 48149 Münster, Germany
| | - Michael Sperling
- Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 30, 48149 Münster, Germany; European Virtual Institute for Speciation Analysis (EVISA), Mendelstraße 11, 48149 Münster, Germany
| | - Astrid Jeibmann
- Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany.
| | - Werner Paulus
- Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany
| | - Thomas Niederstadt
- Department of Clinical Radiology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
| | - Thomas Allkemper
- Department of Clinical Radiology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
| | - Walter Heindel
- Department of Clinical Radiology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
| | - Markus Holling
- Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
| | - Uwe Karst
- Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 30, 48149 Münster, Germany.
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Gomez-Casati DF, Busi MV, Pagani MA. Plant Frataxin in Metal Metabolism. FRONTIERS IN PLANT SCIENCE 2018; 9:1706. [PMID: 30519254 PMCID: PMC6258813 DOI: 10.3389/fpls.2018.01706] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 11/02/2018] [Indexed: 05/08/2023]
Abstract
Frataxin is a highly conserved protein from prokaryotes to eukaryotes. Several functions related to iron metabolism have been postulated for this protein, including Fe-S cluster and heme synthesis, response to oxidative damage and oxidative phosphorylation. In plants, the presence of one or two isoforms of this protein with dual localization in mitochondria and chloroplasts has been reported. Frataxin deficiency affects iron metabolism in both organelles, leading to an impairment of mitochondrial respiration, and chlorophyll and photosynthetic electron transport deficiency in chloroplasts. In addition, plant frataxins can react with Cu2+ ions and dimerize, which causes the reduction of free Cu ions. This could provide an additional defense mechanism against the oxidation of Fe-S groups by Cu ions. While there is a consensus on the involvement of frataxin in iron homeostasis in most organisms, the interaction of plant frataxins with Cu ions, the presence of different isoforms, and/or the localization in two plant organelles suggest that this protein might have additional functions in vegetal tissues.
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Selvadurai LP, Harding IH, Corben LA, Georgiou-Karistianis N. Cerebral abnormalities in Friedreich ataxia: A review. Neurosci Biobehav Rev 2018; 84:394-406. [DOI: 10.1016/j.neubiorev.2017.08.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Revised: 06/06/2017] [Accepted: 08/10/2017] [Indexed: 12/31/2022]
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Navarro JA, Schneuwly S. Copper and Zinc Homeostasis: Lessons from Drosophila melanogaster. Front Genet 2017; 8:223. [PMID: 29312444 PMCID: PMC5743009 DOI: 10.3389/fgene.2017.00223] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 12/11/2017] [Indexed: 01/19/2023] Open
Abstract
Maintenance of metal homeostasis is crucial for many different enzymatic activities and in turn for cell function and survival. In addition, cells display detoxification and protective mechanisms against toxic accumulation of metals. Perturbation of any of these processes normally leads to cellular dysfunction and finally to cell death. In the last years, loss of metal regulation has been described as a common pathological feature in many human neurodegenerative diseases. However, in most cases, it is still a matter of debate whether such dyshomeostasis is a primary or a secondary downstream defect. In this review, we will summarize and critically evaluate the contribution of Drosophila to model human diseases that involve altered metabolism of metals or in which metal dyshomeostasis influence their pathobiology. As a prerequisite to use Drosophila as a model, we will recapitulate and describe the main features of core genes involved in copper and zinc metabolism that are conserved between mammals and flies. Drosophila presents some unique strengths to be at the forefront of neurobiological studies. The number of genetic tools, the possibility to easily test genetic interactions in vivo and the feasibility to perform unbiased genetic and pharmacological screens are some of the most prominent advantages of the fruitfly. In this work, we will pay special attention to the most important results reported in fly models to unveil the role of copper and zinc in cellular degeneration and their influence in the development and progression of human neurodegenerative pathologies such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's Ataxia or Menkes, and Wilson's diseases. Finally, we show how these studies performed in the fly have allowed to give further insight into the influence of copper and zinc in the molecular and cellular causes and consequences underlying these diseases as well as the discovery of new therapeutic strategies, which had not yet been described in other model systems.
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Affiliation(s)
- Juan A. Navarro
- Department of Developmental Biology, Institute of Zoology, University of Regensburg, Regensburg, Germany
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Cook A, Giunti P. Friedreich's ataxia: clinical features, pathogenesis and management. Br Med Bull 2017; 124:19-30. [PMID: 29053830 PMCID: PMC5862303 DOI: 10.1093/bmb/ldx034] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 09/06/2017] [Accepted: 09/19/2017] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Friedreich's ataxia is the most common inherited ataxia. SOURCES OF DATA Literature search using PubMed with keywords Friedreich's ataxia together with published papers known to the authors. AREAS OF AGREEMENT The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets. AREAS OF CONTROVERSY The search for effective disease-modifying agents continues. It remains to be determined whether the most effective approach to treatment lies with increasing frataxin protein levels or addressing the metabolic consequences of the disease, for example with antioxidants. AREAS TIMELY FOR DEVELOPING RESEARCH Management of Freidreich's ataxia is currently focussed on symptomatic management, delivered by the multidisciplinary team. Phase II clinical trials in agents that address the abberrant silencing of the frataxin gene need to be translated into large placebo-controlled Phase III trials to help establish their therapeutic potential.
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Affiliation(s)
- A Cook
- Department of Molecular Neuroscience, Ataxia Centre, UCL Institute of Neurology, Queen Square, London, UK
| | - P Giunti
- Department of Molecular Neuroscience, Ataxia Centre, UCL Institute of Neurology, Queen Square, London, UK
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Bond KM, Brinjikji W, Eckel LJ, Kallmes DF, McDonald RJ, Carr CM. Dentate Update: Imaging Features of Entities That Affect the Dentate Nucleus. AJNR Am J Neuroradiol 2017; 38:1467-1474. [PMID: 28408628 PMCID: PMC7960439 DOI: 10.3174/ajnr.a5138] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The dentate nucleus is a cerebellar structure involved in voluntary motor function and cognition. There are relatively few entities that affect the dentate, and the clinical features of these conditions are often complex and nonspecific. Because these entities are rarely encountered, the formulation of a differential diagnosis can be difficult. Many of the conditions are reversible or treatable with early intervention. Therefore, it is important to recognize classic clinical presentations and their associated characteristic imaging findings. We provide a summary of entities that affect the dentate nucleus and a diagnostic workflow for approaching dentate nucleus imaging abnormalities.
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Affiliation(s)
- K M Bond
- From Mayo Clinic School of Medicine (K.M.B.)
| | - W Brinjikji
- the Department of Radiology (W.B., L.J.E., D.F.K., R.J.M., C.M.C.), Mayo Clinic, Rochester, Minnesota
| | - L J Eckel
- the Department of Radiology (W.B., L.J.E., D.F.K., R.J.M., C.M.C.), Mayo Clinic, Rochester, Minnesota
| | - D F Kallmes
- the Department of Radiology (W.B., L.J.E., D.F.K., R.J.M., C.M.C.), Mayo Clinic, Rochester, Minnesota
| | - R J McDonald
- the Department of Radiology (W.B., L.J.E., D.F.K., R.J.M., C.M.C.), Mayo Clinic, Rochester, Minnesota
| | - C M Carr
- the Department of Radiology (W.B., L.J.E., D.F.K., R.J.M., C.M.C.), Mayo Clinic, Rochester, Minnesota.
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Rasschaert M, Idée JM, Robert P, Fretellier N, Vives V, Violas X, Ballet S, Corot C. Moderate Renal Failure Accentuates T1 Signal Enhancement in the Deep Cerebellar Nuclei of Gadodiamide-Treated Rats. Invest Radiol 2017; 52:255-264. [PMID: 28067754 PMCID: PMC5383202 DOI: 10.1097/rli.0000000000000339] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 10/06/2016] [Indexed: 12/02/2022]
Abstract
OBJECTIVES The purpose of this preclinical study was to investigate whether moderate chronic kidney disease is a factor in potentiating gadolinium (Gd) uptake in the brain. MATERIALS AND METHODS A comparative study was performed on renally impaired (subtotal nephrectomy) rats versus rats with normal renal function. The animals received 4 daily injections of 0.6 mmol Gd/kg a week for 5 weeks (cumulative dose of 12 mmol Gd/kg) of gadodiamide or saline solution. The MR signal enhancement in the deep cerebellar nuclei was monitored by weekly magnetic resonance imaging examinations. One week after the final injection, the total Gd concentration was determined by inductively coupled plasma mass spectrometry in different regions of the brain including the cerebellum, plasma, cerebrospinal fluid, parietal bone, and femur. RESULTS After the administration of gadodiamide, the subtotal nephrectomy group presented a significantly higher T1 signal enhancement in the deep cerebellar nuclei and a major increase in the total Gd concentration in all the studied structures, compared with the normal renal function group receiving the same linear Gd-based contrast agent. Those potentiated animals also showed a pronounced hypersignal in the choroid plexus, still persistent 6 days after the last injection, whereas low concentration of Gd was found in the cerebrospinal fluid (<0.05 μmol/L) at this time point. Plasma Gd concentration was then around 1 μmol/L. Interestingly, plasma Gd was predominantly in a dissociated and soluble form (around 90% of total Gd). Total Gd concentrations in the brain, cerebellum, plasma, and bones correlated with creatinine clearance in both the gadodiamide-treated groups. CONCLUSIONS Renal insufficiency in rats potentiates Gd uptake in the cerebellum, brain, and bones.
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Affiliation(s)
- Marlène Rasschaert
- From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut Curie, Centre de Recherche, PSL Research University; and ‡Université Paris-Sud, Université Paris-Saclay, CNRS, UMR-9187, INSERM, U1196, F-91405, Orsay, France
| | - Jean-Marc Idée
- From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut Curie, Centre de Recherche, PSL Research University; and ‡Université Paris-Sud, Université Paris-Saclay, CNRS, UMR-9187, INSERM, U1196, F-91405, Orsay, France
| | - Philippe Robert
- From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut Curie, Centre de Recherche, PSL Research University; and ‡Université Paris-Sud, Université Paris-Saclay, CNRS, UMR-9187, INSERM, U1196, F-91405, Orsay, France
| | - Nathalie Fretellier
- From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut Curie, Centre de Recherche, PSL Research University; and ‡Université Paris-Sud, Université Paris-Saclay, CNRS, UMR-9187, INSERM, U1196, F-91405, Orsay, France
| | - Véronique Vives
- From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut Curie, Centre de Recherche, PSL Research University; and ‡Université Paris-Sud, Université Paris-Saclay, CNRS, UMR-9187, INSERM, U1196, F-91405, Orsay, France
| | - Xavier Violas
- From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut Curie, Centre de Recherche, PSL Research University; and ‡Université Paris-Sud, Université Paris-Saclay, CNRS, UMR-9187, INSERM, U1196, F-91405, Orsay, France
| | - Sébastien Ballet
- From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut Curie, Centre de Recherche, PSL Research University; and ‡Université Paris-Sud, Université Paris-Saclay, CNRS, UMR-9187, INSERM, U1196, F-91405, Orsay, France
| | - Claire Corot
- From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut Curie, Centre de Recherche, PSL Research University; and ‡Université Paris-Sud, Université Paris-Saclay, CNRS, UMR-9187, INSERM, U1196, F-91405, Orsay, France
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Deistung A, Schweser F, Reichenbach JR. Overview of quantitative susceptibility mapping. NMR IN BIOMEDICINE 2017; 30:e3569. [PMID: 27434134 DOI: 10.1002/nbm.3569] [Citation(s) in RCA: 213] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 05/03/2016] [Accepted: 05/09/2016] [Indexed: 06/06/2023]
Abstract
Magnetic susceptibility describes the magnetizability of a material to an applied magnetic field and represents an important parameter in the field of MRI. With the recently introduced method of quantitative susceptibility mapping (QSM) and its conceptual extension to susceptibility tensor imaging (STI), the non-invasive assessment of this important physical quantity has become possible with MRI. Both methods solve the ill-posed inverse problem to determine the magnetic susceptibility from local magnetic fields. Whilst QSM allows the extraction of the spatial distribution of the bulk magnetic susceptibility from a single measurement, STI enables the quantification of magnetic susceptibility anisotropy, but requires multiple measurements with different orientations of the object relative to the main static magnetic field. In this review, we briefly recapitulate the fundamental theoretical foundation of QSM and STI, as well as computational strategies for the characterization of magnetic susceptibility with MRI phase data. In the second part, we provide an overview of current methodological and clinical applications of QSM with a focus on brain imaging. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Andreas Deistung
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany
| | - Ferdinand Schweser
- Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, NY, USA
- MRI Clinical and Translational Research Center, Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, NY, USA
| | - Jürgen R Reichenbach
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany
- Michael Stifel Center for Data-driven and Simulation Science Jena, Friedrich Schiller University Jena, Jena, Germany
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45
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Abstract
Copper is an essential trace metal that is required for several important biological processes, however, an excess of copper can be toxic to cells. Therefore, systemic and cellular copper homeostasis is tightly regulated, but dysregulation of copper homeostasis may occur in disease states, resulting either in copper deficiency or copper overload and toxicity. This chapter will give an overview on the biological roles of copper and of the mechanisms involved in copper uptake, storage, and distribution. In addition, we will describe potential mechanisms of the cellular toxicity of copper and copper oxide nanoparticles. Finally, we will summarize the current knowledge on the connection of copper toxicity with neurodegenerative diseases.
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Affiliation(s)
- Felix Bulcke
- Center for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, Bremen, Germany
- Center for Environmental Research and Sustainable Technology, Bremen, Germany
| | - Ralf Dringen
- Center for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, Bremen, Germany
- Center for Environmental Research and Sustainable Technology, Bremen, Germany
| | - Ivo Florin Scheiber
- Center for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, Bremen, Germany.
- Center for Environmental Research and Sustainable Technology, Bremen, Germany.
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46
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Dusek P, Schneider SA, Aaseth J. Iron chelation in the treatment of neurodegenerative diseases. J Trace Elem Med Biol 2016; 38:81-92. [PMID: 27033472 DOI: 10.1016/j.jtemb.2016.03.010] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 03/18/2016] [Accepted: 03/21/2016] [Indexed: 01/14/2023]
Abstract
Disturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson's disease.
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Affiliation(s)
- Petr Dusek
- Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Czech Republic; Institute of Neuroradiology, University Göttingen, Göttingen, Germany.
| | | | - Jan Aaseth
- Innlandet Hospital Trust, Kongsvinger, Norway; Hedmark University College, Elverum, Norway
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47
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Soriano S, Calap-Quintana P, Llorens JV, Al-Ramahi I, Gutiérrez L, Martínez-Sebastián MJ, Botas J, Moltó MD. Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease. PLoS One 2016; 11:e0159209. [PMID: 27433942 PMCID: PMC4951068 DOI: 10.1371/journal.pone.0159209] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 06/28/2016] [Indexed: 11/19/2022] Open
Abstract
Friedreich's ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets.
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Affiliation(s)
- Sirena Soriano
- Department of Genetics, University of Valencia, Burjassot, Valencia, Spain
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
| | | | | | - Ismael Al-Ramahi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Lucía Gutiérrez
- Department of Biomaterials and Bioinspired Materials, Instituto de Ciencia de Materiales de Madrid/CSIC, Madrid, Spain
| | | | - Juan Botas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
| | - María Dolores Moltó
- Department of Genetics, University of Valencia, Burjassot, Valencia, Spain
- CIBERSAM, INCLIVA, Valencia, Spain
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48
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Chen K, Lin G, Haelterman NA, Ho TSY, Li T, Li Z, Duraine L, Graham BH, Jaiswal M, Yamamoto S, Rasband MN, Bellen HJ. Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration. eLife 2016; 5:e16043. [PMID: 27343351 PMCID: PMC4956409 DOI: 10.7554/elife.16043] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 06/24/2016] [Indexed: 12/22/2022] Open
Abstract
Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA.
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Affiliation(s)
- Kuchuan Chen
- Program in Developmental Biology, Baylor College of Medicine, Houston, United States
| | - Guang Lin
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Nele A Haelterman
- Program in Developmental Biology, Baylor College of Medicine, Houston, United States
| | - Tammy Szu-Yu Ho
- Department of Neuroscience, Baylor College of Medicine, Houston, United States
| | - Tongchao Li
- Program in Developmental Biology, Baylor College of Medicine, Houston, United States
| | - Zhihong Li
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Lita Duraine
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
| | - Brett H Graham
- Program in Developmental Biology, Baylor College of Medicine, Houston, United States
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Manish Jaiswal
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
| | - Shinya Yamamoto
- Program in Developmental Biology, Baylor College of Medicine, Houston, United States
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States
| | - Matthew N Rasband
- Program in Developmental Biology, Baylor College of Medicine, Houston, United States
- Department of Neuroscience, Baylor College of Medicine, Houston, United States
| | - Hugo J Bellen
- Program in Developmental Biology, Baylor College of Medicine, Houston, United States
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
- Department of Neuroscience, Baylor College of Medicine, Houston, United States
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States
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49
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Kemp KC, Cook AJ, Redondo J, Kurian KM, Scolding NJ, Wilkins A. Purkinje cell injury, structural plasticity and fusion in patients with Friedreich's ataxia. Acta Neuropathol Commun 2016; 4:53. [PMID: 27215193 PMCID: PMC4877974 DOI: 10.1186/s40478-016-0326-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 05/11/2016] [Indexed: 12/05/2022] Open
Abstract
Purkinje cell pathology is a common finding in a range of inherited and acquired cerebellar disorders, with the degree of Purkinje cell injury dependent on the underlying aetiology. Purkinje cells have an unparalleled resistance to insult and display unique regenerative capabilities within the central nervous system. Their response to cell injury is not typical of most neurons and likely represents both degenerative, compensatory and regenerative mechanisms. Here we present a pathological study showing novel and fundamental insights into Purkinje cell injury, remodelling and repair in Friedreich’s ataxia; the most common inherited ataxia. Analysing post-mortem cerebellum tissue from patients who had Friedreich's ataxia, we provide evidence of significant injury to the Purkinje cell axonal compartment with relative preservation of both the perikaryon and its extensive dendritic arborisation. Axonal remodelling of Purkinje cells was clearly elevated in the disease. For the first time in a genetic condition, we have also shown a disease-related increase in the frequency of Purkinje cell fusion and heterokaryon formation in Friedreich's ataxia cases; with evidence that underlying levels of cerebellar inflammation influence heterokaryon formation. Our results together further demonstrate the Purkinje cell’s unique plasticity and regenerative potential. Elucidating the biological mechanisms behind these phenomena could have significant clinical implications for manipulating neuronal repair in response to neurological injury.
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50
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Li K, Reichmann H. Role of iron in neurodegenerative diseases. J Neural Transm (Vienna) 2016; 123:389-99. [PMID: 26794939 DOI: 10.1007/s00702-016-1508-7] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 01/12/2016] [Indexed: 01/01/2023]
Abstract
Currently, we still lack effective measures to modify disease progression in neurodegenerative diseases. Iron-containing proteins play an essential role in many fundamental biological processes in the central nervous system. In addition, iron is a redox-active ion and can induce oxidative stress in the cell. Although the causes and pathology hallmarks of different neurodegenerative diseases vary, iron dyshomeostasis, oxidative stress and mitochondrial injury constitute a common pathway to cell death in several neurodegenerative diseases. MRI is capable of depicting iron content in the brain, and serves as a potential biomarker for early and differential diagnosis, tracking disease progression and evaluating the effectiveness of neuroprotective therapy. Iron chelators have shown their efficacy against neurodegeneration in a series of animal models, and been applied in several clinical trials. In this review, we summarize recent developments on iron dyshomeostasis in Parkinson's disease, Alzheimer's disease, Friedreich ataxia, and Huntington's disease.
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Affiliation(s)
- Kai Li
- Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstr. 74, 01307, Dresden, Germany.
| | - Heinz Reichmann
- Department of Neurology, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstr. 74, 01307, Dresden, Germany
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