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.

The Fragile X gene (FMR1) is polymorphic for the number of CGG trinucleotide repeats in its 5’-untranslated region. Repeat sizes in the general population range between 5-55 CGG repeats. In Fragile X syndrome repeat expansions exceed 200, silencing expression of FMR1, resulting in intellectual disability. Carriers of the Fragile X premutation have between 55-200 repeats in the FMR1 gene and are at risk for developing Fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a late onset neurodegenerative disorder causing tremor, ataxia, brain pathology, cognitive loss, dementia and early death in some individuals. The proposed pathological mechanism is a toxic RNA gain-of-function model in which mRNAs containing expanded CGG repeats accumulate in neuronal nuclear aggregates. These RNA aggregates sequester specific RNA-binding proteins, thus impairing their normal cellular functions and ultimately resulting in neuronal death. Currently, no treatment exists for FXTAS. As the potential molecular target is well defined (i.e. the mutant FMR1 mRNA), FXTAS is highly amenable to the development of gene targeting therapy. Therefore, the primary objective of this proposal is (1) to establish critical developmental periods when disease might be halted or reversed and (2) to identify pharmacological and molecular compounds to alleviate expanded CGG-induced toxicity. Collectively, the partners of this multidisciplinary consortium have excellent in vivo and in vitro models of FXTAS, valuable resources and state-of-the-art and emerging technologies available.