25–30 May 2020, Spetses Island, Greece
Neuromuscular disorders (NMD) are highly heterogeneous diseases, both clinically and genetically, for which no treatment is available as yet. In order to conceive and develop therapeutic approaches for these disorders, a comprehensive knowledge of their natural history (clinical, histopathology, genetics, biochemical defects) and a refined comprehension of the underlying pathophysiological mechanisms are essential.
Our team research topics focus mainly on 2 groups of NMDs: collagen type VI-related muscle disorders & ECM-related disorders and Emery-Dreifuss muscular dystrophies & other striated muscle laminopathies. These NMDs that could be named as ‘contractile myopathies’, share some symptoms and may be differential diagnosis for one another. A complementary area of research is centered on mechanobiology defects in muscular disorders, an important feature in our NMDs of interest.
Our previous activities have led to the identification of genetic defects, the development of tools (cellular and animal models) and the exploration of pathomechanistic hypotheses for the better comprehension of the molecular bases of these NMDs and the discovery of therapeutic targets. Many questions concerning these diseases remain unanswered: absence of molecular diagnosis for a subset of patients, implicated protein function and pathophysiological mechanisms… Several common points (contractile dysfunction, mecanobiology defects, fibrosis…) have been and are still being addressed transversally through pooling our specific expertises (nucleus, extracellular matrix, contractile proteins…).
Our team’s project revolves around 3 axes: 1) defining the genetic and clinical spectrum and the natural history of these NMDs; 2) investigating pathophysiological mechanisms of gene mutations that induce these cardiac and/or skeletal muscle affections with the overall goal to 3) identify and test therapeutic avenues for these disorders.
Our research topics are carried out on biological material from patients (DNA, RNA, cultured cells (primary and immortalized skin fibroblasts, myoblasts) and biopsies) as well as various animal models (Knock-in Lmna and Col6 mouse models, Zebrafish models) we developed for each of the NMDs of interest. We also developed 3D culture models of primary and immortalized myoblasts.
1. Bertrand AT, Renou L, Papadopoulos A, Beuvin M, Lacène E, Massart C, Ottolenghi C, Decostre V, Maron S, Schlossarek S, Cattin ME, Carrier L, Malissen M, Arimura T, Bonne G. DelK32-lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death. Hum Mol Genet. 2012 Mar 1;21(5):1037-48.
2. Cattin ME, Bertrand AT, Schlossarek S, Le Bihan MC, Skov Jensen S, Neuber C, Crocini C, Maron S, Lainé J, Mougenot N, Varnous S, Fromes Y, Hansen A, Eschenhagen T, Decostre V, Carrier L, Bonne G. Heterozygous LmnadelK32 mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity. Hum Mol Genet. 2013 Aug 1;22(15):3152-64.
3. Bertrand AT, Ziaei S, Ehret C, Duchemin H, Mamchaoui K, Bigot A, Mayer M, Quijano-Roy S, Desguerre I, Lainé J, Ben Yaou R, Bonne G, Coirault C. Cellular micro-environments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors. J Cell Sci. 2014 Jul 1;127(Pt 13):2873-84. (selected for the Cover of the issue of the journal).
4. Vassilopoulos S, Gentil C, Lainé J, Buclez PO, Franck A, Ferry A, Précigout G, Roth R, Heuser JE, Brodsky FM, Garcia L, Bonne G, Voit T, Piétri-Rouxel F, Bitoun M. Actin scaffolding by clathrin heavy chain is required for skeletal muscle sarcomere organization. J Cell Biol. 2014 May 12;205(3):377-93.
5. Perovanovic J, Dell'Orso S, Gnochi VF, Jaiswal JK, Sartorelli V, Vigouroux C, Mamchaoui K, Mouly V, Bonne G, Hoffman EP Laminopathies disrupt epigenomic developmental programs and cell fate. Sci Transl Med. 2016 Apr 20;8(335):335ra58.
25–30 May 2020, Spetses Island, Greece