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Testing novel tetracyclines in models of a severe mitochondrial disease

Objectifs

The goal of this study is to determine whether novel tetracyclines (TCs) can block the pathology in a model of mitochondrial disease using behavioral, histological and molecular techniques. This will provide an important proof-of-principle for future clinical development of TCs in severe mitochondrial brain diseases.
 

Résumé

Leigh syndrome (LS) is a fatal mitochondrial condition characterized by severe neurometabolic defects. No treatment is currently available for this disease because of the limited capability of drugs and viral vectors to cross the blood-brain barrier. Our team recently demonstrated that the use of a novel brain-penetrating viral vector provides a robust therapeutic benefit in a mouse model of LS (Reynaud et al. 2020, Brain). However, as the suitability of this new viral vector in humans is unclear, alternative strategies must be explored.
Pharmacological approaches represent an attractive option as they can target relevant molecular pathways. Our collaborators (Pr. Auwerx; EPFL, Lausanne) demonstrated that tetracyclines (TCs), a family of antibiotics, trigger the mitochondrial unfolded protein which is a physiological protective response (Houtkooper et al., 2013, Nature). While TCs poorly cross the blood-brain barrier, they recently identified a novel TC that penetrate the brain 300-fold better. This prompts us to test the effect of this new TC in models of LS.
 

Méthodes

The M2 student will perform the following techniques: mouse breeding, genotyping, drug treatment, weight and temperature monitoring, behavioral tests, tissue extraction, brain cutting, histology, immunostaining, microscopy, image analysis, protein dosage, western blot and cell culture.
 

Références

  • Reynaud-Dulaurier et al. (2020) Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome Brain, in press.
  • Houtkooper et al. (2013) Mitonuclear protein imbalance as a conserved longevity mechanism. Nature, (497): 451-59.

Domaines d'expertise requis

No specific prior expertise is needed. The student will learn what is new for her/him.

Contacts

M. Decressac, Researcher UGA / Group leader
Email : michael.decressac@univ-grenoble-alpes.fr
Tél : 04 56 52 06 75
 

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Mise à jour le 26 juin 2020

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