Mitochondrial Risk Factors in Parkinson's Disease

• Applicant: Privatdozent Manu Sharma, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392376548

The aim of this project is to gain essential knowledge with respect to the contribution of genetic variability of nuclear-encoded mitochondrial proteins to the pathogenesis of PD via (i) elucidation of rare genetic risk variants, (ii) identification of mitochondrial phenotypes that contribute to PD pathogenesis and (iii) analysis of their potentialsuitability as novel therapeutic targets. To disentangle the complex genetic architecture of PD, we will investigate mitochondrial network perturbations in idiopathic PD.Here we will use advanced computational modelling approaches to build a mitochondrial molecular network from public, tissue-specific protein-protein interaction andgene regulatory data. This network will then be used to integrate a unique set of genetic and transcriptomic data, which is accessible through applicant memberships in different worldwide genetic consortia, via dedicated statistical network analyses. Newly identified risk variants will be validated in PD patient cohorts by high throughputgenotyping technologies and, after burden analyses and prioritisation, patient-based cellular models will be generated from the relevant samples for the functional characterisation of mitochondrial phenotypes in neurons related to PD pathogenesis. The outcome of this project will be the identification of PD-related mitochondrial risk variants that act in common pathways and their validation as new targets for future therapeutic approaches, leading to tailored stratified therapies. The resulting PD models from this project will be directly fed into a translational pipeline at the LCSB, including a unique automation platform funded by the FNR for compound screening of FDA approved drugs to correct the PD-related phenotypes within the concept of repurposing of drugs for individualised therapies.

• DFG Programme: Research Grants
• International Connection: Luxembourg
• Co-Investigator: Professor Dr. Rejko Krüger