Objective: Integrate available genetic and expression data to generate a molecular landscape of Parkinson’s disease (PD) in order to identify key disease mechanisms that may provide clues for novel treatment targets.

Background: PD is caused by a complex interplay of genetic and environmental factors. In order to provide new insights into the pathophysiological mechanisms underlying the disease, we have integrated the available genetic and expression data to generate a molecular landscape of PD.

Methods: We conducted genetic network and elaborate literature analyses of the top-ranked findings from 13 published genome-wide association studies (GWASs) of PD (involving 13.094 cases and 47.148 controls) and genes implicated in PD through other evidence, including familial PD candidate gene association and mRNA/protein expression studies in PD patients.

Results: The molecular PD landscape, located in dopaminergic (DA) neurons and multiple immune cell types, harbors four main biological processes: oxidative stress response, lysosomal function, endoplasmic reticulum stress response and immune response activation. These processes interact with each other and regulate DA neuron function and death, the pathological hallmark of PD. Of note, lipoproteins, lipids and lipid metabolites are functionally involved in and influenced by all these processes, and affect DA neuron-specific molecular cascades. Furthermore, epidemiological findings and our GWAS data-based polygenic risk score analyses indicate a shared environmental and genetic risk between lipid and lipoprotein traits and PD.

Conclusions: The constructed molecular PD landscape highlights the key role of lipids and lipoproteins in PD pathogenesis and provides clues for drug targets that modulate lipid and lipoprotein signalling, allowing for the development of novel disease-modifying treatments for PD.

Part of these data was presented at AD/PD 2015.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/molecular-landscape-of-parkinsons-disease-reveals-a-key-role-for-lipids-and-lipoproteins/