Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia
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A picture is emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex, which should foster the development of new strategies for the treatment of FRDA.Abstract:
Friedreich’s ataxia (FRDA) is the most prevalent autosomic recessive ataxia and is associated with a severe cardiac hypertrophy and less frequently diabetes. It is caused by mutations in the gene encoding frataxin (FXN), a small mitochondrial protein. The primary consequence is a defective expression of FXN, with basal protein levels decreased by 70–98%, which foremost affects the cerebellum, dorsal root ganglia, heart and liver. FXN is a mitochondrial protein involved in iron metabolism but its exact function has remained elusive and highly debated since its discovery. At the cellular level, FRDA is characterized by a general deficit in the biosynthesis of iron-sulfur (Fe-S) clusters and heme, iron accumulation and deposition in mitochondria, and sensitivity to oxidative stress. Based on these phenotypes and the proposed ability of FXN to bind iron, a role as an iron storage protein providing iron for Fe-S cluster and heme biosynthesis was initially proposed. However, this model was challenged by several other studies and it is now widely accepted that FXN functions primarily in Fe-S cluster biosynthesis, with iron accumulation, heme deficiency and oxidative stress sensitivity appearing later on as secondary defects. Nonetheless, the biochemical function of FXN in Fe-S cluster biosynthesis is still debated. Several roles have been proposed for FXN: iron chaperone, gate-keeper of detrimental Fe-S cluster biosynthesis, sulfide production stimulator and sulfur transfer accelerator. A picture is now emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. These findings should foster the development of new strategies for the treatment of FRDA. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.read more
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Journal ArticleDOI
Neuroinflammation in Friedreich’s Ataxia
TL;DR: Evidence about the involvement of neuroinflammatory-related mechanisms in models of Friedreich's ataxia is discussed and clues for the modulation of glial- related mechanisms as a possible strategy to improve disease features are provided.
Journal ArticleDOI
Iron Insertion at the Assembly Site of the ISCU Scaffold Protein Is a Conserved Process Initiating Fe-S Cluster Biosynthesis.
B. Srour,Sylvain Gervason,Maren Hellen Hoock,Beata Marta Monfort,K K Want,Djabir Larkem,Nadine Trabelsi,Gautier Landrot,Andrea Zitolo,Emiliano Fonda,Emilien Etienne,Guillaume Gerbaud,Christina S. Müller,Jonathan Oltmanns,Jesse B. Gordon,Vishal Yadav,Malgorzata Kleczewska,Marcin Jelen,Michel B. Toledano,Rafal Dutkiewicz,David P. Goldberg,Volker Schünemann,Bruno Guigliarelli,Bénédicte Burlat,Christina Sizun,Benoît D'Autréaux +25 more
TL;DR: In this article , it was shown that the insertion of a ferrous iron in the assembly site of ISCU proteins is a conserved mechanism and that the iron center is coordinated by four strictly conserved amino acids, i.e., Cys35, Asp37, Cys61, and His103.
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Book ChapterDOI
Advances in Iron Retrograde Signaling Mechanisms and Uptake Regulation in Photosynthetic Organisms.
TL;DR: In this paper , the authors discuss recent advances in the characterization of the mechanisms of Fe homeostasis and Fe retrograde signaling in photosynthetic organisms, and discuss how to maintain and regulate adequate concentrations of this metal in response to physiological needs.
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Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich’s Ataxia Pre-Clinical Models and Clinical Trials
TL;DR: In this paper , the authors overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies.
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Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion
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TL;DR: A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.
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Alexandra Durr,Mireille Cossée,Yves Agid,Victoria Campuzano,Claude Mignard,C. Penet,Jean-Louis Mandel,Alexis Brice,Michel Koenig +8 more
TL;DR: The clinical spectrum of Friedreich's ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion on chromosome 9 is useful for diagnosis, determination of prognosis, and genetic counseling.
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Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia.
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