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Mitochondriale Risikofaktoren in der Parkinson-Krankheit

Fachliche Zuordnung Molekulare und zelluläre Neurologie und Neuropathologie
Förderung Förderung von 2018 bis 2021
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 392376548
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

Mitochondrial dysfunction has long been recognized as an early and causative event in PD pathogenesis. Earlier studies showed increased PD risk in subjects exposed to mitochondrial toxins followed by genetic studies unequivocally implicating early-onset forms of PD and mutations in distinct gene products (e.g. PINK1, Parkin) playing a major role in mitochondrial function and quality control. Interestingly, hallmarks of mitochondrial dysfunction have also been observed in cellular models established from sporadic PD patients, showing defective oxidative phosphorylation, increased oxidative stress, and mitochondrial DNA (mtDNA) damage. Neurodegeneration in such sporadic PD patients cannot be explained by aging or environmental factors alone, which possibly implies the existence of pathogenic variants in mitochondrial genes. This project aims to gain essential knowledge concerning the contribution of nuclear-encoded mitochondrial genes to the pathogenesis of PD via (i) elucidation of genetic risk variants, (ii) identification of mitochondrial phenotypes that contribute to PD pathogenesis, and (iii) analysis of their potential suitability as novel therapeutic targets. To disentangle the complex genetic architecture of PD, we investigated mitochondrial network perturbations in idiopathic PD (iPD) patients. To meet our objectives, we applied advanced computational modelling approaches and genotyping data from different worldwide consortia to identify mitochondrial risk factors potentially involved in PD pathogenesis. Importantly, newly discovered risk variants have been functionally validated in patient-based cellular models, allowing us to define specific mitochondrial pathways and phenotypes related to PD pathogenesis. This will help to dissect the heterogeneous group of iPD patients into pathogenic subtypes – in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden – potentially eligible for future precision medicine therapeutic approaches.

Projektbezogene Publikationen (Auswahl)

 
 

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