DEcipher the ComplexIty and Plasticity of epigenomic cHaracteristics under influence of Environmental factors in the pathomechanistic Regulation of PD – decipherPD

As the most common neurodegenerative movement disorder, Parkinson’s Disease (PD) represents a major clinical and societal burden, leading to progressive locomotor deficits, loss of dopaminergic neurons in the midbrain, and poor quality of life for the patients. The hallmark neuropathologic feature of the disease is the accumulation of α-synuclein (SNCA) protein aggregates in Lewy bodies in the PD brain. Rare SNCA point mutations and genomic multiplications are linked to familial PD cases with high penetrance and therefore constitute major genetic risk factors for PD. However, the preponderance of PD cases is apparently sporadic, suggesting the involvement of epigenomic factors for the development of PD and synucleinopathies. Moreover, the association of other environmental factors including aging, high fat diet and stress, further underscores the importance for the consideration of epigenomic mechanisms in PD etiology and progression. Here we take a multi-omics approach to comprehensively profile the PD epigenome across multiple layers. Firstly, we reveal the epigenomic characteristics of SNCA-related alterations before we, secondly, extend our efforts to a large cohort of idiopathic PD patients to compare our findings against. Specifically, we will assess epigenomic regulation including histone modifications, DNA methylation and hydroxymethylation in well-characterized transgenic SNCA mouse and cell models as well as in primary tissues from PD patients. Parallel transcriptomic profiling will be performed to link epigenetic dysregulation to gene expression changes. Furthermore, we will interrogate the plasticity of epigenomic modifications under the influence of environmental factors using longitudinal cohorts of sporadic PD cases and mouse models exposed to standardized and specific environmental factors. In a health-oriented approach, we will integrate this rich set of generated pan-omics data in order to identify key targets of dysregulation on the genomic as well as epigenomic level. The unprecedented breadth of this data set will enable sophisticated systems-analyses to reveal master regulators and pathway hubs that drive and interconnect key cellular circuits involved in disease pathology. Drawing on the power of induced pluripotent stem cells and LUHMES cell models for PD, we will validate our in silico predictions. Collectively, these efforts will not only advance our understanding of the disease towards a systems-level regarding the interplay between environment, epigenome, PD pathology, but also pinpoint targets in the pathomechanistic orchestration that could open up novel avenues to much-needed therapeutics for this still incurable disease.