Polyglutamine expansion diseases: from pathomechanisms to therapeutic strategies
Polyglutamine (PolyQ) expansion diseases are a group of 9 adult-onset genetic disorders that result in progressive degeneration of brain areas specific to each disease. PolyQ diseases are caused by the expansion of unstable CAG trinucleotide repeats, which code for polyQ expansion in ubiquitously expressed disease proteins. Cognate wild type proteins bear a polymorphic polyQ, while expansion above a certain polyQ length threshold (around 35-40Q), confer toxic properties to mutant proteins. A correlation exists between polyQ length and disease severity: the larger the polyQ expansion, the more toxic is the mutant protein. There is yet no effective therapy to prevent or slow down pathogenic processes of these diseases.
Our laboratory is interested in unraveling the pathophysiological mechanisms of two polyQ diseases : Huntington’s Disease (HD) and SpinoCerebellar Ataxia 7 (SCA7). HD is the most frequent polyQ diseases with a prevalence of around 1 affected to 12 000 individuals. HD causes involuntary motor movements and cognitive decline, and results from the progressive degeneration of the striatum and some cortical layers. SCA7 is unique among polyQ diseases as it causes progressive retinal degeneration together with cerebellar atrophy, leading to blindness and ataxia. Comparison between these two diseases allows us to identify disease-specific and common pathomechnanisms.
Our objectives are : 1) to determine why expanded polyQ motifs are toxic by studying their structural and aggregation properties ; 2) to unravel the cellular and molecular mechanisms of toxicity in HD and SCA7; 3) to develop strategies to stimulate the clearance of toxic mutant proteins or to prevent toxic aggregation.
We address these fundamental and medical questions by combining biochemistry, biophysics, cell biology and « Omic » approaches, by analyzing cellular, mouse and zebrafish disease models and by using these models to develop therapeutic strategies.
- To characterize and to understand the pathophysiology of HD and SCA7 in relevant mouse models
- To unravel a new function of ataxin-7 in zebrafish
- To determine the role of protein interactors of ataxin-7 and huntingtin in the pathogenesis of SCA7 and HD
- To determine the relationship between polyQ length, structure and toxicity
- To determine the mechanisms of clearance of polyQ-expanded proteins
- To develop strategy to prevent the toxic accumulation/aggregation of polyQ-expanded proteins
- Marina Yefimova, Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St-Petersburg
- Uwe Wolfrum, Cell and Matrix Biology, Johannes Gutenberg University of Mainz
- Katrin Lindenberg, Department of Neurology, University of Ulm
- Anne Bertolotti, Lab Molecular Biologie-Neurobiology, Cambridge
- Patricia Maciel: Institute for Molecular and Cell Biology, University of Porto
- Michel Roux, Translational medicine and Neurogenetic programme, IGBMC, Université de Strasbourg, Illkirch ;
- Alicia Torriglia, Inserm UMRS 872, Physiopathologie des maladies oculaires : innovations thérapeutiques, Paris
- David Hicks, CNRS UPR 3212, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg
- Annie Sittler, ICM, Paris
- Pascal Villa, Plateforme de Chimie Biologique Intégrative de Strasbourg
- Danièle Altschuh, Biocapteurs, Ecole Supérieure de Biotechnologie de Strasbourg Illkirch
- Bruno Kieffer, Structural Biology and Genomics programme, IGBMC,
- Alberto Podjarny, Structural Biology and Genomics programme, IGBMC
- Julien Vermot, Development and Stem Cells programme, IGBMC
- Michel Roux, Translational medicine and Neurogenetic programme, IGBMC
- Hélène Dollfus, Laboratoire Physiopathologie des Syndromes Rares Hereditaires, Strasbourg
- Bénédicte Durand, Centre de Génétique et de Physiologie Moléculaires et Cellulaires, CNRS UMR 5534, Université Claude Bernard Lyon 1
- Nicolas Bourmeyster, Signalisation et Transports Ioniques Membranaires (STIM) FRE 3511 CNRS,Université de Poitiers
- Yvon TROTTIER - Scientific prize - Comité Alsace de la Fondation pour la Recherche Médicale (FRM) - 2014
Hum Mol Genet Aug. 4, 2016 .
Biochim Biophys Acta Sep 2016 ; 1862:1558-69 .
Neurobiol Dis May 16, 2015 ; 80:15-28 .
J Mol Biol June 19, 2015 ; 427:2166-78 .
Front Neurol Feb. 4, 2015 ; 6:14 .
Hum Mol Genet Oct. 15, 2013 ; 22:4215-23 .
PLoS Genet Nov 2012 ; 8:e1003051 .
Hum Mol Genet July 15, 2011 ; 20:2795-806 .
Pathol Biol (Paris) Oct 2010 ; 58:357-66 .
Zh Evol Biokhim Fiziol. 2010 ; 46:414-417 .
- Post Doc - Equipe Y.Trottier (H/F)
- Developing Strategies That Increase Clearance Of Mutant Ataxin-7 And Prevent Its Toxic Accumulation In Spinocerebellar Ataxia 7 (H/F)
- Molecular Basis Of Transcriptional Dysregulations In The Spinocerebellar Ataxia 7, A Neurodegenerative Polyglutamine Disorder. (H/F)