Despite the advances in the identification of genes involved in Parkinson’s disease (PD), there are still
appreciable gaps in our understanding of the mechanisms underlying the neurodegenerative process
and its relation to environmental factors in PD. Therefore we are proposing a comprehensive
approach based on (i) a unique collection of families with autosomal dominant and autosomal
recessive PD and (ii) large cohorts of clinically well-defined sporadic PD patients from different
populations worldwide for (iii) genetic studies and (iv) assessment of environmental modifiers that will
translate into (v) functional validation studies in patient-derived cellular models. Using next
generation sequencing strategies including exome sequencing in multiplex families and
targeted resequencing in sporadic PD patients, we will disentangle the complex genetic architecture
of PD in different populations and attempt to better define the underlying functional variants in
disease-associated GWAS loci. Newly identified genetic variants are filtered for pathogenic relevance
based on novel prediction algorithms combined with unique expression databases and
replicated in large cohorts of PD patients . Here the Genetic Epidemiology of Parkinson’s disease
Consortium (GEO-PD) provides a unique resource with a large number of DNA samples and
environmental exposure data of PD patients and controls from different populations worldwide.
Subsequent assessment of disease modifiers includes two complementary approaches: Mendelian
randomization , and gene-environment interaction studies . In order to validate genetic risk
variants, functional studies on patient-based material will be performed. Here the applicants
provide unique expertise for fibroblasts- and induced-pluripotent-stem-cells-(iPSC)-derived
cellular models of PD and a large repository of biomaterials from carriers of PD-associated
mutations. Established readouts allow to study functional effects of identified genetic risk factors and
will be used to assign novel disease genes and risk variants to defined pathogenic pathways.
Moreover patient-based cellular models will be challenged with environmental risk factors identified
as modulators of disease . We expect that the combination of comprehensive state-of-the-art genetic
technologies with a detailed ascertainment of environmental modifiers will provide important clues to
decipher the complexity of neurodegeneration in PD. Subsequent modelling of PD in patient-based
material allows to discover molecular mechanisms and pathways involved and leading to therapies
for this still incurable disease.