PI leader: Marc Bartoli, DR CNRS.

Taskforce: Sébastien Courrier IGE , Nathalie Da Silva AI , Alizée Dangreaux PhD student, Sabrina Beaumier IGE. Associated clinicians : Shahram Attarian PUPH, Emmanuelle Campana-Salort PH, Svetlana Gorokhova MCUPH, Martin Krahn PUPH.

Muscular dystrophies and myopathies form a significant part of our research focus, with our efforts geared towards understanding how genetic mutations lead to muscle degeneration. These conditions result in progressive loss of muscle strength and function, making them a major cause of disability.

"Our research on muscular dystrophies is centered on uncovering the precise molecular mechanisms that underlie muscle breakdown. By identifying these pathways, we aim to develop targeted therapies, such as gene therapy and cellular treatments, to restore muscle function and slow disease progression." Marc Bartoli

The team is also working to enhance genetic diagnosis methods, making it easier to detect and understand these diseases at earlier stages. The development of new therapeutic approaches, such as gene editing, is a key part of our strategy to provide patients with life-changing treatment options.

This program is funded by INSERM and the AFM-Téléthon.

We are always looking for motivated and talented young researchers, do not hesitate to join us to share your ideas!

Selected publications:

- O. Ballouhey, M. Chapoton, B. Alary, S. Courrier, N. Da Silva, M. Krahn, N. Levy, N. Weisleder and M. Bartoli. “A dysferlin exon 32 nonsense mutant mouse model shows pathological signs of dysferlinopathy” Biomedicines 2023, 11, 1438

- O. Ballouhey, S. Courrier, V. Kergourlay, S. Gorokhova, M. Cerino, M. Krahn, N. Lévy and M. Bartoli. “The dysferlin transcript containing the alternative exon 40a is essential for myocyte functions “Front Cell Dev Biol. 2021 Nov 23;9:754555.

- M. Cerino, E. Campana-Salort, A. Salvi, P. Cintas, D. Renard, RJ. Morales, C. Tard, F. Leturcq, T. Stojkovic, N. Bonello-Palot, S. Gorokhova, J. Mortreux, AM De Paula, N. Lévy, J. Pouget, M. Cossée, M. Bartoli, M. Krahn, S. Attarian. “Novel CAPN3 variant associated with an autosomal dominant calpainopathy“. Neuropathol Appl Neurobiol. 2020;10.1111/nan.12624.

- J-P. Desvignes, M. Bartoli, V. Delague, M. Krahn, M. Miltgen, C. Béroud and D. Salgado. VarAFT: a variant annotation and filtration system for human next generation sequencing data. Nucleic Acids Res. 2018 Jul 2;46(W1): W545-W553.

- F. Barthélémy, C. Blouin, N. Wein, V. Mouly, S. Courrier, E. Dionnet, V. Kergourlay, Y. Mathieu, L. Garcia, G. Butler-Browne, C. Lamaze, N. Lévy, M. Krahn and M. Bartoli. Exon 32 Skipping of Dysferlin Rescues Membrane Repair in Patients’ Cells. Journal of neuromuscular diseases. 2015 2;(2): 281-290

- Böhm J, Chevessier F, Maues De Paula A, Koch C, Attarian S, Feger C, Hantaï D, Laforêt P, Ghorab K, Vallat JM, Fardeau M, Figarella-Branger D, Pouget J, Romero  NB, Koch M, Ebel C, Levy N, Krahn M, Eymard B, Bartoli M, Laporte J. Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy. Am J Hum Genet. 2013 Feb 7;92(2):271-8. PubMed PMID: 23332920

- Krahn M.  Lostal W, Wein N, Bartoli M, Courrier S, Bourg-Alibert N, Nguyen K, Vial C, Streichenberger N, Labelle V, DePetris D, Pécheux C, Leturcq F, Cau P, Richard I and Lévy N. A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy. Sci Transl Med. 2010 Sep 22;2(50):50ra69. PubMed PMID: 20861509

- Lostal W, Bartoli M, Bourg N, Roudaut C, Bentaïb A, Miyake K, Guerchet N, Fougerousse F, McNeil P, Richard I. Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Hum Mol Genet. 2010 May 15;19(10):1897-907. PubMed PMID: 20154340.  

- Bartoli M, Gicquel E, Barrault L, Soheili T, Malissen M, Malissen B, Vincent-Lacaze N, Perez N, Udd B, Danos O, Richard I. Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation. Hum Mol Genet. 2008 May 1;17(9):1214-21. PubMed PMID: 18252745.  

- Fougerousse F*, Bartoli M*, Poupiot J, Arandel L, Durand M, Guerchet N, Gicquel E, Danos O, Richard I. Phenotypic correction of alpha-sarcoglycan deficiency by intra-arterial injection of a muscle-specific serotype 1 rAAV vector. Mol Ther. 2007 Jan;15(1):53-61. PubMed PMID: 17164775.   

- Bartoli M, Roudaut C, Martin S, Fougerousse F, Suel L, Poupiot J, Gicquel E,  Noulet F, Danos O, Richard I. Safety and efficacy of AAV-mediated calpain 3 gene  transfer in a mouse model of limb-girdle muscular dystrophy type 2A. Mol Ther. 2006 Feb;13(2):250-9. PubMed PMID: 16290124.   

PI leader: Nathalie Bernard-Marissal, CRCN

Taskforce: Marine Tessier, Engineer; Zeinab Hamze, Postdoc, Setrida El Hachem, PhD student (co-supervision with Valérie Delague)

Charcot-Marie-Tooth disease (CMT) is a rare, incurable genetic disorder of the peripheral nervous system. CMTs are subdivided according to the cell type initially affected (Schwann cell or motor neuron/sensory neuron) and their genetic origin. To date, over 120 CMT-related genes have been identified, encoding proteins with diverse biological functions. This genetic heterogeneity makes it difficult to develop a common therapy for several CMTs.

With a view to developing effective therapies, our objectives are to 

(1) discover new therapeutic targets by defining key molecular/cellular pathways linked to CMT subtypes or potentially shared by several forms

(2) develop new therapies based on pharmacological or genetic approaches.

We are particularly focusing on genes involved in mitochondria-ER functions and inter-organelle communication associated with motor/sensory neuron dysfunction (MFN2/CMT2A, GDAP/CMT2K, etc.) as well as genes linked to myelination defects (FGD4/CMT4H). Using induced pluripotent stem cell-derived motor/sensory neurons from patients as well as transgenic mouse models, we are defining new key molecular targets by combining transcriptomic and proteomic approaches.

At the same time, we are testing pharmacological approaches targeting mitochondria-ER contacts and ER stress, and setting up high-throughput screening of compounds in the chemical library to reveal potential new therapies.

Finally, we are also developing individualized gene therapies aimed at counteracting the defective gene in the right cell type or cell compartment, using adeno-associated viral vectors.

This program is funded by the ANR and INSERM young researcher grants, and by the AFM-Téléthon.

We are always looking for motivated and talented young researchers, do not hesitate to join us to share your ideas!

Selected publications

Lara El Bazzal, [...] Valérie Delague, Nathalie Bernard-Marissal^*, Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H, BRAIN, doi: 10.1093/brain/awac402.

Cylia Rochat, Nathalie Bernard-Marissal et al., Expression of a miRNA targeting mutated SOD1 in astrocytes induces motoneuron plasticity and improves neuromuscular function in ALS mice, Glia. 2022 Jan 3. doi: 10.1002/glia 

Nathalie Bernard-Marissal et alAltered interplay between endoplasmic reticulum and mitochondria in Charcot-Marie-Tooth type 2A neuropathy, PNAS, 2019 Feb 5;116(6):2328-2337. doi: 10.1073/pnas

Nathalie Bernard-Marissal et al., Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration Brain. 2015 Apr;138(Pt 4):875-90. doi: 10.1093/brain/awv008.