Fundamental and pathophysiological mechanisms implicated in recessive ataxia
Recessive ataxias are neurodegenerative disorders that affect the cerebellum and/or the spinal cord. Recessive ataxias represent a heterogeneous set of severely disabling neurological disorders estimated to affect 1/20,000 individuals in Europe. Our research focuses on recessive ataxias that are linked to two essential mitochondrial pathways: iron-sulfur cluster (ICS) biosynthesis and coenzyme Q10 (CoQ10) biosynthesis.
Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by progressive gait and limb ataxia associated with hypertrophic cardiomyopathy and an increase incidence in diabetes. The major mutation is a GAA repeat expansion within the first intron of the FXN gene. FRDA belongs to the family of trinucleotide repeat disorders, including Huntington’s disease (with a CAG expansion) or myotonic muscular dystrophy type 1 (with a CTG expansion). Trinucleotide repeats are dynamic mutations that show instability (expansion/contraction) in the germline and in selective somatic cells. In FRDA, the GAA expansion leads to heterochromatinization of the locus resulting in a drastic decrease of transcription of FXN. The disease results from loss of function of FXN gene product, frataxin, a highly conserved mitochondrial protein involved in the biogenesis of ISC, which are essential protein cofactors implicated in numerous cellular functions.
The autosomal recessive cerebellar ataxia 2 (ARCA2) is characterized by cerebellar ataxia and atrophy, and is associated with exercise intolerance. Most patients present a mild deficiency in CoQ10 in muscle biopsies. ARCA2 results from loss of function mutations in the ADCK3 gene that encodes a mitochondrial protein with unknown function related to CoQ10 biosynthesis.
Our laboratory is interested in unraveling the pathophysiological mechanisms implicated in these recessive ataxias, and understanding the function of the proteins in the ISC and CoQ10 biosynthesis pathways, respectively. Finally, we aim at developing therapeutic approaches to cure these devastating diseases.
We address these fundamental and medical questions by combining human genetics, mouse genetics, biochemistry, molecular and cell biology, induced pluripotent stem cell (iPSC) technology and gene therapy.
• To characterize and understand the pathophysiology of recessive ataxias using mouse models (FRDA, ARCA2)
• To unravel the function of frataxin in the mammalian ISC biosynthesis
• To unravel the function of ADCK3 in CoQ10 biosynthesis
• To develop cellular models using culture of primary neurons from mouse or iPSC technology to obtain cardiac and neuronal cells
• To develop innovative therapeutic approaches for FRDA using gene therapy
• P. Aubourg and N. Cartier (St Vincent de Paul Hospital, Paris)
• C. Bouton (Institut de Chimie des Substances Naturelles, Gif sur Yvette)
• R. Festenstein (Imperial College London, London, UK)
• J. Fontecilla and Y. Nicolet (Institut de Biologie Structurale, Grenoble)
• M. Hentze and B. Galy (EMBL, Heidelberg, Germany)
• D. R. Lynch (Philadelphia, USA)
• R. Mendel and F. Bittner (Braunschweig, Germany)
• A. Munnich and A. Rötig (Necker Hospital, Paris)
• S. Ollagnier de Choudens (CEA, Grenoble)
• M. Pandolfo (Brussels, Belgium)
• F. Pierrel (CEA, Grenoble)
• H. Puy (Centre Français des Porphyries, Paris)
- Hélène Puccio - Prix Antoine Lacassagne - Collège de France - 2016
- Hélène PUCCIO - Scientific award - Académie Rhénane - 2014
- Stéphane SCHMUCKER - Thesis Prize - Société de Biologie de Strasbourg - 2010
- Alain MARTELLI - Young Investigator Award - National Ataxia Foundation - 2010
- Hélène PUCCIO - Dr. Jean Toy Prize - Institut de France de l'Académie des Sciences - 2008
- Stéphane SCHMUCKER - Jean-Claude Stoclet Prize - Faculté de Pharmacie de Strasbourg - 2008
- Hélène PUCCIO - ERC Starting grant - European Research Council (ERC) - 2007
- Hélène PUCCIO - Pediatric Pathology Research Senior Prize - Association pour l'Etude de la Pathologie Pédiatrique - 2004
- Hélène PUCCIO - Young Investigator Award - National Ataxia Foundation - 2003
- Feb. 4, 2015 - Friedreich’s ataxia: a useful iron accumulation for cells…
- April 6, 2014 - Friedreich's ataxia – an effective gene therapy in an animal model
- Feb. 11, 2013 - Toward understanding of Friedreich's ataxia
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Neurology Dec. 8, 2015 ; 85:2026-35 .