PRIMA

Dysfunctions of mitochondria and the autophagy-lysosomal pathway (ALP) take part in the pathologic process of Parkinson’s disease (PD) and are induced by most PD-associated mutations. This project aims at shedding light on the involvement of mitochondrial DNA (mtDNA) mutations and the role of the FLCN/MiT pathway in the context of various PD-related mutations in patient-derived neurons. Two main tasks are pursued to achieve these objectives: 1) The involvement of the mitochondrial genome in PD etiology is being defined through in-depth genetic analyses of the mtDNA, including sequencing, copy number and deletion assays in patient-derived cells and differentiated neurons. In addition, cytoplasmic hybrids carrying mtDNA variants in the context of PD-related mutations will provide insight into the functional role of mtDNA variations. 2) The FLCN-MiT signaling cascade will be assessed for its role in linking mitochondrial and ALP functions in PD and its potential as pharmacological target for PD and other neurodegenerative diseases. Overall, this project will describe alterations in PD that can be exploited as potential pharmacological targets at the intersection between mitochondrial and ALP functions.