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Dysfunctional mitochondria as a neuronal pathogen

Descrizione del progetto

L’RNA mitocondriale indiziato per le malattie mitocondriali

I mitocondri sono organuli eucarioti che producono la maggior parte dell’energia delle cellule. La disfunzione mitocondriale influisce sul metabolismo cellulare e provoca le malattie mitocondriali che sembrano influire in particolare sul sistema nervoso che richiede energia elevata. Il progetto MitoTROJAN, finanziato dall’UE, lavorerà sull’ipotesi secondo cui l’RNA mitocondriale a doppio filamento (mtdsRNA, mitochondrial double-stranded RNA) sia implicato nella neuropatologia delle malattie mitocondriali. I ricercatori adotteranno un approccio multidisciplinare e, utilizzando un modello murino delle malattie mitocondriali, studieranno i meccanismi della risposta immunitaria associati a mtdsRNA. I risultati amplieranno le attuali conoscenze sull’eziologia delle malattie mitocondriali e individueranno nuovi bersagli terapeutici con potenziale applicativo nell’ambito della neurodegenerazione.

Obiettivo

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 In addition, unpublished results of the host group showed that this neuronal population develop a robust cellular antiviral-like response elicited by mitochondrial double-stranded RNA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.

Coordinatore

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

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Regione
Este Cataluña Barcelona
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 172 932,48