Team 4: Huntington’s disease: Neurophysiopathology from drosophila to mice

The research carried out in the team "Neurophysiopathology from Drosophila to mice" developed in the MMDN includes several axes. These studies concerned several neurodegenerative diseases, including Huntington's disease, Amyotrophic Lateral Sclerosis and Alzheimer's disease, with pathological phenotypes in common, such as the formation of amyloid deposits or aggregates, and defects in the energy metabolism of mitochondria. These diseases also have specificities, which allowed us to address several aspects of these diseases, with the advantages of the different fields of competence of the team’s members.

The aim of these studies is to better understand the physiological role of proteins involved in the diseases and to identify and study therapeutic peptides against these disorders. Several strategies are envisaged using multiple in silico and in vitro approaches (Cyrille Garnier, Lecturer, University of Rennes), in cellulo (Nathalie Bonneaud, IR1 CNRS), but also in vivo in Drosophila or in mice (Jean-Charles Liévens, CR1 CNRS; Florence Maschat, DR2 CNRS).

Although several themes are developed by the various protagonists, the main theme of the team is the analysis and development of the therapeutic peptide P42 which is protective of Huntington's disease (F. Maschat, Patent PCT / FR2012 / 050809; Orphan drugs by the European Medicines Agency (EMA / COMP / 275974/2015). The current studies on P42 concern the analysis of its physiological role as an Huntingtin domain, but also on the molecular details of its protective effects on the formation of the aggregates or on the neuronal activity (F. Maschat, N. Bonneaud, C. Garnier). For therapeutic purposes, a preclinical maturation study of P42 is under development. Finally, 2nd generation peptides with greater stability, permeability and efficiency are currently developed (F. Maschat, N. Bonneaud, JC Liévens).

Aim 1 - Engrailed, un acteur majeur du développement neuronal (F. Maschat)

Aim 2 - P42, a therapeutic peptide against Huntington’s disease(F. Maschat)

Aim 3 - Quality control of mitochondria in neurodegenerative diseases (J.C. Liévens)

Aim 4 - Pathological peptides and therapeutic peptides (C. Garnier)

Aim 5 - Chaperone proteins in neurodegenerative diseases (C. Garnier)

Florence Maschat, scientific officer

Research Director CNRS Contact: florence.maschat(at)umontpellier.fr Phone: 33 (0)4 67 14 42 70

Jean-Charles Lievens

Research Fellow CNRS Contact :jean-charles.lievens(at)umontpellier.fr Phone: 04 67 14 39 80

Cécilia Marelli

PH CHU Contact: c-marelli(at)chu-montpellier.fr Phone: 04 67 14 42 70

• Couly, S., Paucard A., Bonneaud, N., Maurice, T., Benigno, L., Jourdan, C., Vignes, M., Maschat, F. (2018). Improvement of BDNF signalling by P42 peptide in Huntington's disease. Human Molecular Genetics 27(17):3012-3028.
• Bonneaud, N.,Layalle, S., Colomb, S., Jourdan, C., Ghysen, A., Severac, D., Dantec, C, Nègre, N., Maschat, F. (2017) Control of nerve cord formation by Engrailed and Gooseberry−Neuro: a multi−step coordinated process. Developmental Biology 432 : 273–285.
• Arribat, Y., Talmat-Amar, Y., Paucard, A., Lesport, P., Bonneaud, N., Bauer. C., Bec, N., Parmentier, ML., Benigno, L., Larroque, C., Maurel, P. and Maschat, F. (2014) Systemic delivery of P42 peptide: a new weapon to fight Huntington's disease. Acta Neuropathologica Communications 2: 86-103
• Arribat, Y., Bonneaud, N., Talmat-Amar, Y., Layalle, S., Parmentier, M. L., and Maschat, F. (2013) A Huntingtin Peptide Inhibits PolyQ-Huntingtin Associated Defects. PLoS ONE 8(7): e68775
• Layalle, S., Volovitch, M. Mugat, B. Bonneaud, N. Parmentier, M.L., Prochiantz A., Joliot, A. and Maschat, F. (2011) Engrailed homeoprotein acts as a signaling molecule in the developing fly. Development 138:2315-2323.
• Godin, J.D., Poizat, G., Hickey, M.A., Maschat, F., and Humbert, S. (2010) Mutant huntingtin-impaired degradation of beta-catenin causes neurotoxicity in Huntington's disease. EMBO J. Jul 21;29(14):2433-45.
• Mugat, B., Parmentier, M-L, Bonneaud, N., Chan H.O.E., and Maschat, F. (2008) Protective role of Engrailed in a Drosophila model of Huntington’s disease. Human Molecular Genetics, 17(22), 3601- 3616.