Title of the project : Causes of weight loss in amyotrophic lateral sclerosis
Project : Amyotrophic lateral sclerosis (ALS) is a rare progressive neurodegenerative disease that affects thousands of adults each year. It is estimated that approximatively 8000 people in France are diagnosed with the disease. This dramatic condition is clinically characterized by a progressive paralysis, due to degeneration of motor neurons, leading to death with 3 to 5 years after symptom onset. To date, there is a complete lack of therapeutic options for ALS patients besides riluzole, that modestly improves survival, and symptomatic treatments.
A number of ALS cases are genetically inherited, and four major genes have been associated to the disease (SOD1, TARDBP, FUS and C9ORF72). Besides motor system impairment, most ALS patients suffer from premorbid weight loss, that can be dramatic with disease progression, and whose magnitude is inversely correlated with survival. Our laboratory aims at understanding the causes of this early symptom. We first demonstrated the occurrence of hypothalamic alterations during disease in both ALS patients and mouse models (Vercruysse et al. Brain. 2016 Apr;139(Pt 4):1106-22; Gorges, Vercruysse et al, JNNP 2017). Furthermore, increasing caloric intake of ALS patients was associated with prolonged survival in fast progressing patients (Ludolph et al. Ann. Neurol. 2019 in press). We now would like to understand the cellular and molecular aspects of the metabolic changes in ALS patients to propose new therapeutic routes to treat the disease.
This 3-years funded PhD is an ambitious project within an international team, that will allow you to work from the gene to models and to the patient. The project will be developed within the newly built institute CRBS (Centre de Recherche en Biomédecine de Strasbourg), in an Inserm and Université de Strasbourg joint laboratory.
Candidate profile : We are looking for a young scientist in Neuroscience, not scared of the challenge. Knowledge in neuroanatomy, pharmacology, genetics and metabolism are highly regarded.
Big data mining and programming and/or physiology background will also be very appreciated but not fundamental. The position is opened for any candidates worldwide. The working language is English. French skills are not essential but helpful. Strasbourg is a highly international and dynamic city at the heart of European Union. Please send one PDF file including a cover letter detailing your path, a CV with academic marks, and three academic references name to:
Application : Dr. Luc Dupuis ldupuis@neuro-cnrs.unistra.fr and Dr. Matei Bolborea matei.bolborea@inserm.fr
Selected publications of the laboratory:
- Ludolph AC, Dorst J, Dreyhaupt J, Weishaupt JH, Kassubek J, Weiland U, Meyer T, Petri S, Hermann A,
- Emmer A, Grosskreutz J, Grehl T, Zeller D, Boentert M, Schrank B, Prudlo J, Winkler AS, Gorbulev S, Roselli F, Schuster J, DUPUIS L; LIPCAL-ALS Study Group. Effect of High-Caloric Nutrition on Survival in Amyotrophic Lateral Sclerosis. Ann Neurol. 2019 Dec 17. doi: 10.1002/ana.25661.
- Picchiarelli G*, Demestre M*, Zuko A, Been M, Higelin J, Dieterlé S, Goy MA, Mallik M, Sellier C, Scekic-Zahirovic J, Zhang L, Rosenbohm A, Sijlmans C, Aly A, Mersmann S, Sanjuan-Ruiz I, Hübers AM, Messaddeq N, Wagner M, van Bakel N, Boutillier AL, Ludolph AC, Lagier-Tourenne C, Boeckers TM#, DUPUIS L #, Storkebaum E# FUS-mediated transcriptional regulation of acetylcholine receptor at neuromuscular junctions is compromised in amyotrophic lateral sclerosis, Nat Neurosci, 2019 Nov;22(11):1793-1805. doi: 10.1038/s41593-019-0498-9. (#: co-senior authors)
- V ercruysse P , Sinniger J, El Oussini H, Scekic-Zahirovic J, Dieterlé S, Dengler R, Meyer T , Zierz S, KassubekJ, Fischer W, DreyhauptJ, GrehlT, HermannA, Grosskreutz J, Witting A, Van Den Bosch L, Spreux-Varoquaux O, Ludolph A.C. & DUPUIS L. Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis, Brain. 2016, Apr;139(Pt 4):1106-22.
- El Oussini H, Bayer H, Scekic-Zahirovic J, Vercruysse P, Sinniger J, Dirrig-Grosch S, Dieterlé S, Echaniz- Laguna A, Larmet Y, Müller K, Weishaupt JH, Thal DR, van Rheenen W, van Eijk K, Lawson R, Monassier L, Maroteaux L, Roumier A, Wong PC, van den Berg LH, Ludolph AC, Veldink JH, Witting A & DUPUIS L. Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis. Acta Neuropathol. 2016, 131(3):465-80
- Scekic-Zahirovic J., Sendscheid O., El Oussini H., Jambeau M., Ying S., Mersmann S., Wagner M., Dieterlé S., Sinniger J., Dirrig-Grosch S., Drenner K., Birling M.C., Qiu J., Zhou Y., Li H., Fu X.D., Rouaux C., Shelkovnikova T., Witting A., Ludolph A.C., Kiefer F., Storkebaum E., Lagier-Tourenne C. & DUPUIS L.Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss EMBO J., 2016, 35(10):1077-97. doi: 10.15252/embj.201592559