| Autor: |
Klemann CJHM; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Nijmegen, The Netherlands., Martens GJM; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Nijmegen, The Netherlands., Sharma M; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany., Martens MB; Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands., Isacson O; Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, Belmont, MA USA., Gasser T; Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany., Visser JE; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Nijmegen, The Netherlands.; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Neurology, Amphia Hospital, Breda, The Netherlands., Poelmans G; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Nijmegen, The Netherlands.; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. |
| Abstrakt: |
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-oxidative stress response, endosomal-lysosomal functioning, endoplasmic reticulum stress response, and immune response activation-that 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. |
