%0 Journal Article
%T Integrated molecular landscape of Parkinson¡¯s disease
%A C. J. H. M. Klemann
%A G. J. M. Martens
%A G. Poelmans
%A J. E. Visser
%A M. B. Martens
%A M. Sharma
%A O. Isacson
%A T. Gasser
%J Archive of "NPJ Parkinson's Disease".
%D 2017
%R 10.1038/s41531-017-0015-3
%X Parkinson¡¯s disease is caused by a complex interplay of genetic and environmental factors. Although a number of independent molecular pathways and processes have been associated with familial Parkinson¡¯s disease, a common mechanism underlying especially sporadic Parkinson¡¯s disease is still largely unknown. In order to gain further insight into the etiology of Parkinson¡¯s disease, we here conducted genetic network and literature analyses to integrate the top-ranked findings from thirteen published genome-wide association studies of Parkinson¡¯s disease (involving 13.094 cases and 47.148 controls) and other genes implicated in (familial) Parkinson¡¯s disease, into a molecular interaction landscape. The molecular Parkinson¡¯s disease landscape harbors four main biological processes¡ªoxidative stress response, endosomal-lysosomal functioning, endoplasmic reticulum stress response, and immune response activation¡ªthat interact with each other and regulate dopaminergic neuron function and death, the pathological hallmark of Parkinson¡¯s disease. Interestingly, lipids and lipoproteins are functionally involved in and influenced by all these processes, and affect dopaminergic neuron-specific signaling cascades. Furthermore, we validate the Parkinson¡¯s disease -lipid relationship by genome-wide association studies data-based polygenic risk score analyses that indicate a shared genetic risk between lipid/lipoprotein traits and Parkinson¡¯s disease. Taken together, our findings provide novel insights into the molecular pathways underlying the etiology of (sporadic) Parkinson¡¯s disease and highlight a key role for lipids and lipoproteins in Parkinson¡¯s disease pathogenesis, providing important clues for the development of disease-modifying treatments of Parkinson¡¯s disease
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460267/