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Dysfunctional mitochondria as a neuronal pathogen

Description du projet

L’ARN mitochondrial, suspect présumé dans les maladies mitochondriales

Les mitochondries sont des organites eucaryotes qui produisent la majorité de l’énergie des cellules. Le dysfonctionnement mitochondrial affecte le métabolisme cellulaire et entraîne des maladies mitochondriales qui semblent affecter particulièrement le système nerveux, consommateur de grandes quantités d’énergie. Le projet MitoTROJAN, financé par l’UE, travaillera sur l’hypothèse selon laquelle l’ARN mitochondrial double brin (ARNmtdb) est impliqué dans la neuropathologie des maladies mitochondriales. Les chercheurs adopteront une approche pluridisciplinaire et, par le biais d’un modèle murin de maladies mitochondriales, ils étudieront les mécanismes de la réponse immunitaire associés à l’ARNmtdb. Les résultats contribueront à élargir les connaissances actuelles sur l’étiologie des maladies mitochondriales et identifieront de nouvelles cibles thérapeutiques qui pourraient avoir des applications dans la neurodégénérescence.

Objectif

The symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity. Due to its archeobacterial origin, mitochondria has been posited as a potential source of molecules that can elicit cellular responses to pathogens. Among other key functions, mitochondria generates most of the energy required by cells. Alterations in components of the mitochondrial energy-generating machinery lead to primary mitochondrial disease (MD), a group of highly invalidating human conditions with no effective treatment. High-energy-requiring cells, such as neurons, are especially affected in MD. However, not all neuronal populations are equally affected and the molecular determinants of this susceptibility are currently unknown. Recently, Quintana´s lab uncovered that GABAergic neurons in the Globus Pallidus (GPe) of a mouse model of Leigh syndrome (LS) are particularly sensitive to MD leading to fatal encephalopathy, recapitulating the human pathology. In addition, unpublished results of the host group showed that this neuronal population develop a robust cellular antiviral-like response elicited by mitochondrial double-stranded RNA (mtdsRNA). Nevertheless, the contribution of mtdsRNA release in the MD progression has never been defined. Thus, the main goal of MitoTROJAN is to identify the effect of mtdsRNA-induced neuropathology in the context of mitochondrial dysfunction with the overarching goal of providing novel targets for the treatment of MD. By combining mouse genetics with cutting-edge molecular biology and multi-omics approach, I will carry out a multidisciplinary strategy to i) parse the molecular mechanisms of mtdsRNA-induced neuropathology and ii) characterise the antiviral response-induced protein shutdown in affected neurons. Overall results will provide new insight on an uncharacterized mechanism of mitochondria-mediated neurodegeneration and will help to identify novel therapeutic targets for MD and other neurodegenerative diseases.

Coordinateur

UNIVERSITAT AUTONOMA DE BARCELONA
Contribution nette de l'UE
€ 172 932,48
Adresse
EDIF A CAMPUS DE LA UAB BELLATERRA CERDANYOLA V
08193 Cerdanyola Del Valles
Espagne

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Région
Este Cataluña Barcelona
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 172 932,48