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 FXNgene. 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 FXNgene 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/COQ8Agene that encodes a mitochondrial protein with a regulatory role in CoQ10 biosynthesis.
The current project of the team are the following:
- Towards increasing diagnostics for cerebellar ataxia and identification of novel genes
Combining clinical and genetic expertise, we are developing new diagnostics tools and identify novel genes for cerebellar ataxia. We are performing next generation sequencing to find new genes in cohorts of recessive cerebellar ataxia as well as sporadic late onset cerebellar ataxias. All new candidate genes are validated by functional studies. - Towards a better understanding of the pathophysiology of Friedreich Ataxia (FA) and Cerebellar ataxia with CoQ10 deficiency (ARCA2)
Our goals are to better define the function of the disease proteins and to decipher the cellular and molecular pathways involved in the diseases. We are studying faithful mouse, zebrafish and cell model of the diseases, using a wide range of techniques from biochemistry and Omics (transcriptomic, epigenomic, proteomic, metabolomics) to functional and behavioural analyses. - Identification and validation of biomarkers for FA and ARCA2
We aim at investigating in a systematic manner the blood and plasma composition along disease progression in mouse models and in patients using high-throughput technics. The detection of these alterations in circulating fluids provides an opportunity to identify and establish relevant biomarkers of disease onset and progression. - Developing pre-clinical therapeutic approaches
To pinpointing therapeutic targets, we are developing cell-based high-throughput screening (HTS) strategies, to identify novel genes, pathways or drugs targeting sophisticated readouts, specifically tailored for FA and ARCA2. We profit of our panel of in vivodisease models to validate and further assess the promising targets. In parallel, advance candidate drugs, including gene therapy approaches, are directly tested in our already established mouse models using quantitative phenotypic parameters.
Publications
- 1. Schmucker S., Martelli A., Colin F., Page A., Wattenhofer-Donzé M., Reutenauer L., and Puccio H. (2011) Mammalian frataxin : an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PlosOne 6(1):e16199.
- 2. Martelli A., Friedman L.S., Reutenauer L., Messaddeq N., Perlman L., Lynch DR, Fedosov K., Schulz J.B., Pandolfo M., Puccio H. (2012) Clinical data and characterization of the liver conditional mouse model exclude neoplasia as a non-neurological manifestation associated with Friedreich’s ataxia Disease Models and Mechanisms 5(6):860-9
- 3. Hick A, Wattenhofer-Donzé M, Chintawar S, Tropel P, Simard JP, Vaucamps N, Gall D, Lambot L, André C, Reutenauer L, Rai M, Teletin M, Messaddeq N, Schiffmann SN, Viville S, Pearson CE, Pandolfo M, Puccio HM. (2012) Neurons and cardiomyocytes derived from induced pluripotent stem cell as a model for mitochondrial defects in Friedreich’s ataxia. Disease Models and Mechanisms 6(3):608-21.
- 4. Colin F, Martelli A, Clémancey M, Latour JM, Gambarelli S, Zeppieri L, Birck C, Page A, Puccio H, Ollagnier de Choudens S. (2013) Mammalian Frataxin Controls Sulfur Production and Iron Entry during de Novo Fe(4)S(4) Cluster Assembly. J Am Chem Soc. 135(2):733-40.
- 5. Perdomini M, Belbellaa B, Monassier L., Reutenauer L., Messaddeq N, Cartier N., Crystal R., Aubourg P., Puccio H. (2014) Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia Nature Medicine 20(5):542-7.
- 6. Martelli A., Schmucker S., Reutenauer L., Mathieu J., Peysonnaux C., Karim K., Puy H., Galy B., Hentze M., Puccio H. (2015) Iron Regulatory Protein 1 sustains mitochondrial iron loading and function in frataxin deficiency Cell Metabolism 21(2): 311-322
- 7. Stefely J.#, Licitra F.#, Laredj L., Reidenbach A., Kemmerer Z., Grangeray A., Jaeg T., Minogue C., Ulbrich A., Hutchins P., Wilkerson E., Ruan Z., Aydin D., Hebert A., Guo X., Freiberger E., Reutenauer L., Jochem A., Chergova M., Johnson I., Lohman D., Rush M., Kwiecien N., Singh P.K., Schlagowski A., Floyd B., Forsman U., Sindelar P., Westphall M., Pierrel F., Zoll J., Dal Peraro M., Kannan N., Bingman C., Coon J., Isope P., Puccio H.*, Pagliarini D.* (2016) Cerebellar Ataxia and Coenzyme Q Deficiency Through Loss of Unorthodox Kinase Activity. Molecular Cell63(4):608-20
# equal contribution * co-corresponding - 8. Beilschmidt L.K., Ollagnier de Choudens S., Fournier M., Sanakis I., Hograindleur M.A., Clémancey M., Blondin G., Schmucker S., Eisenmann A., Weiss A., Koebel P., Messaddeq N., Puccio H.*, Martelli A. * (2017) ISCA1 is essential for mitochondrial Fe4-S4 biogenesis in vivo. Nature Communication 8 :15124
*co-corresponding - 9. Piguet F., de Montigny C., Vaucamps N., Reutenauer L., Eisenmann A., Puccio H. (2018) Rapid and complete reversal of sensory ataxia by gene therapy in a novel model of Friedreich ataxia.Molecular Therapy 26(8):1940-1952
- 10. Belbellaa B, Reutenauer L., Monassier L., Puccio H. (2019) Correction of half the cardiomyocytes fully rescue Friedreich Ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms.Human Molecular Genetics 28(8):1274-1285