The Team
  • Researchers

    Aurore HICK

    Karine MERIENNE

    Hélène PUCCIO

  • Post-Doctoral Fellowships

    Mayada ACHOUR JREDA

    Brahim BELBELLAA

    Leila LAREDJ

    Alain MARTELLI

    Françoise PIGUET

    Pankaj Kumar SINGH

  • Phd Students

    Lena Kristina BEILSCHMIDT

    Tiphaine JAEG

  • Engineers & Technicians

    Charline DE MONTIGNY

    Laurence REUTENAUER

    Nadège VAUCAMPS

Translational medicine and neurogenetics

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. Furthermore, we are interested in understanding the in vivo dynamics of CAG and GAA repeats associated to diseases. 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.

Imprimer Envoyer

Université de Strasbourg
INSERM
CNRS

IGBMC - CNRS UMR 7104 - Inserm U 964
1 rue Laurent Fries / BP 10142 / 67404 Illkirch CEDEX / France Tél +33 (0)3 88 65 32 00 / Fax +33 (0)3 88 65 32 01 / directeur.igbmc@igbmc.fr