Unravelling Parkinson's disease pathways
While the common form of PD is sporadic, certain mutations cause Mendelian forms of PD. This group of rare inherited diseases is further divided into autosomal dominant and recessive forms, each characterised by a specific set of mutations. The molecular basis of common PD can be unravelled by studying how these genetic defects lead to PD progression. The 'European project on Mendelian forms of Parkinson's disease' (MEFOPA) initiative focused on identification and validation of disease-related molecular pathways, drug targets and biomarkers for disease susceptibility and progression. Mendelian PD was used as a model to study pathogenic molecular mechanisms and pathways. Work involved three sub-projects. The first focused on pathogenic mechanisms caused by the mutations in the dominant genes, which were found to interconnect. Autosomal-recessive mutations, studied in the second sub-project, contributed to the state of increased cellular stress, mitochondrial dysfunction and increased radical oxygen species. These results, obtained on cell lines and animal models, were further validated in patient samples and ex vivo cells in the third sub-project. Symptomatic and asymptomatic patients were organised into a European registry, resulting in the largest cohort of patients with Mendelian PD. The registry enabled comparison of different Mendelian forms with healthy controls cross-sectionally and longitudinally. A biobank for body fluids, cells and tissues from patients was established in order to identify the biomarkers of the disease. Transcriptional and proteomic changes in ex vivo cells from patients with Mendelian PD were evaluated in great detail. MEFOPA obtained information about the pathogenic pathways on transcriptomic, proteomic and biochemical levels. Specific biomarkers for Mendelian forms of PD were identified. This knowledge, along with creation of the largest worldwide registry for PD mutation carriers, sets the stage for interventional trials. Thus, a genetic cohort with autosomal dominant form of PD carrying alpha synuclein mutations is now being used in a new EU Seventh Framework Programme (FP7) project, MULTISYN — an exploratory interventional study using the antibody therapeutics approach.
Keywords
Parkinson's disease, neuroprotective, Mendelian, autosomal, mutations, genetic defects, molecular pathways, alpha synuclein
