Hereditary ataxias are a heterogeneous set of severely disabling neurological disorders caused by degeneration of the cerebellum and/or the spinal cord. The prevalence of hereditary ataxias is estimated to 1/20,000 individuals in Europe, and yet there are no specific treatments for most of them.

Our research focuses on understanding the pathophysiology of ataxia, discovering disease biomarkers and developing therapeutic approaches. In addition, in close collaboration with the clinicians, we are developing new diagnostics tools for cerebellar ataxia and identify novel genes causing ataxia.

We are mainly interested in two different recessive ataxias, Friedreich ataxia (FA) and autosomal recessive cerebellar ataxia 2 (ARCA2), linked to two essential mitochondrial pathways: iron-sulfur cluster (ICS) biosynthesis and coenzyme Q10 (CoQ10) biosynthesis, respectively; FA belongs to the family of trinucleotide repeat disorders, which are caused by dynamic mutations that show instability (expansion/contraction) in the germline and in selective somatic cells.

Friedreich ataxia (FA), 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. In FA, 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/COQ8A gene that encodes a mitochondrial protein with a regulatory role in CoQ10 biosynthesis.

Key words: ataxia, mitochondria, genetics, models (cell, mouse, zebrafish), therapeutic approaches

The central goal of our team is to understand how the excitability of neurons and muscles is regulated by basic molecular and cellular processes that control the biology of potassium-selective ion channels.

To identify novel genes and conserved cellular processes that regulate the biology of potassium channels in vivo, we take advantage of the powerful genetic tools available in the model nematode Caenorhabditis elegans. We use the full array of techniques available in C. elegans including genetics, live imaging, electrophysiology and state-of-the-art CRISPR/Cas9 genome engineering and next-generation DNA sequencing.

Our team studies the cellular and molecular basis sustaining neuronal integrity, and deciphers the mechanisms underlying neurodegeneration and/or developmental defects in disease.

Initially focused on a fatal neurodegenerative disease called GAN (giant axonal neuropathy), we identified the encoded Gigaxonin-E3 ligase and uncovered its pivotal roles in controlling cytoskeletal architecture (Intermediate Filaments), autophagy machinery (ATG16L1) and neuronal identity (Shh signaling through Ptch). Our scientific direction is to further tackle the biology of neuromuscular diseases. Specifically, we aim to unravel the regulations and functions of i) the cytoskeleton and ii) the autophagy pathway in normal neuronal physiology and disease states, and then translate this knowledge into therapies.

Our team is strongly engaged in the dissemination of science (fundamental & translational), and organizes/participates to numerous events for the public and patients.