CASyM winter school of Systems Medicine took place between March 29th and April 1st 2017 in Ljubljana, Slovenia and is entitled »The 3rd SysBioMed hands-on tutorial: Systems Medicine Approaches in Personalized Medicine«
Genetic variability in pathways defective in Parkinson's disease: possible applications
Sara Redenšek1,Maja Trošt2,Vita Dolžan1
1Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Slovenia,2Department of Neurology, University Medical Centre Ljubljana, Slovenia
Introduction: Parkinson's disease (PD) is a neurodegenerative brain disorder mostly affecting dopaminergic neurons by dopamine depletion and α-synuclein aggregation within neurons, which are two main pathological hallmarks of the disease. Main signs and symptoms of PD are bradykinesia, rest tremor, rigidity and postural impairment. By the time clinical diagnosis is made, 80% of dopaminergic neurons is already irreversibly lost. However, the course of PD largely differs between patients [1, 2]. That is why there is a great need for biomarkers for early diagnosis, disease prognosis, and drug response, for new drug targets, and for new treatment regimens allowing for personalized medicine. Our aim was to search the published data for genetic factors associated with PD risk and treatment outcome, to elucidate the underlying molecular pathways, and to search for genes and genetic variants, especially functional single nucleotide polymorphisms (SNPs) as potential biomarkers of disease susceptibility, disease prognosis and drug response. Methods and results: We performed a literature synthesis of genome wide association studies (GWAS) that investigated PD susceptibility. We identified 24 loci, which are implicated in different cellular pathways. For each locus we assigned a cellular pathway in which it is mostly involved. Seven pathways were found to be associated with PD susceptibility: protein aggregation; protein and membrane trafficking; lysosomal autophagy; immune system; neurodevelopment, neuron cell differentiation and survival; mitochondrial homeostasis; and other processes . We used these potentially corrupted pathways as a platform for choosing SNPs, that could be tested either for evaluating disease prognosis or drug response. Common functional SNPs in candidate genes from dopamine pathway (COMT, MAO-B, DDC, SLC6A3, SLC22A1, DRD2, DRD3), immune response pathway (NLRP3, CARD8, IL1B, IL6, TNF), oxidative stress (SOD2, CAT, GPX1, NOS1) and neurodevelopment, neuron cell differentiation and survival pathways (BDNF, NOTCH4, NRG1) were identified. Conclusion: From GWAS results, which usually point out non-functional intergenic variants, we identified most significant pathways of PD pathogenesis. Furthermore, we established that dopamine pathway, immune response pathway, oxidative stress, and neurodevelopment, neuron cell differentiation and survival pathways harbour common functional SNPs that warrant further studies as potential biomarkers of disease susceptibility, disease prognosis and drug response. The presented approach allows to find ways of personalizing PD management. References: 1. Kalia, L.V. and A.E. Lang, (2015) Lancet 386(9996), p.896-912. 2. Poewe, W., et al., (2017) Nat Rev Dis Primers 3(17013), p.13. 3. Redenšek, S., M. Trošt, and V. Dolžan, (2017) Frontiers in Aging Neuroscience, 9(20).
2006 - University of Ljubljana, Faculty of Medicine, Center for Functional Genomics and Bio-chips.