The current projects of the team are the following :

1. 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.
2. 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.
3. 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.
4. 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 Cell 63(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

Fundings

• Fondation pour la Recherche Médicale 2021-2024 – “AtaxiaXplorer – Common pathways underlying Purkinje neuron degeneration in Cerebellar Ataxias”
• European Joint Programme on Rare Diseases 2021-2024 – “TREAT-ARCA – Designing a toolbox of paradigmatic treatments for a targeted molecular medicine approach to autosomal-recessive ataxias”
• Friedreich’s Ataxia Research Alliance 2021-2023 – “Defining the therapeutic window and threshold for neuronal gene therapy in Friedreich Ataxia”
• Association Française de l’Ataxie de Friedreich 2021 – “Uncovering novel pathophysiological pathways misregulated in the neuropathology of Friedreich Ataxia”