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Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease.
Dis Model Mech. 2017 05 01; 10(5):619-631.DM

Abstract

Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3'-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.

Authors+Show Affiliations

Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany. NDAL, Boğaziçi University, Istanbul 34342, Turkey.Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany. NDAL, Boğaziçi University, Istanbul 34342, Turkey.Department of Neurology, Philipps University, Baldingerstrasse, Marburg 35043, Germany.Dr Senckenberg Chronomedical Institute, Goethe University, Frankfurt/Main 60590, Germany.Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.Department of Neurology, Haydarpaşa Numune Training and Research Hospital, Istanbul 34668, Turkey.Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, Dresden 01307, Germany.NDAL, Boğaziçi University, Istanbul 34342, Turkey.Institute of Human Genetics, Heinrich Heine University, Düsseldorf 40225, Germany.Department of Neurology, Philipps University, Baldingerstrasse, Marburg 35043, Germany.Department of Molecular Neurobiology and Center for the Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, Göttingen 37075, Germany.Department of Molecular Neurobiology and Center for the Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, Göttingen 37075, Germany.Department of Pathology and Medical Biology, Medical Center, University, Groningen 9700 RB, The Netherlands.Buchmann Institute for Molecular Life Sciences and Institute for Biophysics, Goethe University, Frankfurt/Main 60438, Germany.Haemophilia Centre, Medical Clinic III, Institute of Immunohaematology and Transfusion Medicine, Goethe University, Frankfurt/Main 60590, Germany.Department of Internal Medicine, Division of Vascular Medicine and Hemostaseology, Goethe University, Frankfurt 60590, Germany.Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität, Dresden 01307, Germany.Department of Neurology, RWTH Aachen University Hospital, Aachen 52074, Germany.Department of Sleep Medicine and Neuromuscular Disorders, University Hospital Münster, Münster 48149, Germany.Department of Neurology, Philipps University, Baldingerstrasse, Marburg 35043, Germany.Buchmann Institute for Molecular Life Sciences and Institute for Biophysics, Goethe University, Frankfurt/Main 60438, Germany.Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, Dresden 01307, Germany.Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.Dr Senckenberg Chronomedical Institute, Goethe University, Frankfurt/Main 60590, Germany.NDAL, Boğaziçi University, Istanbul 34342, Turkey.Department of Neurology, Philipps University, Baldingerstrasse, Marburg 35043, Germany.Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany auburger@em.uni-frankfurt.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28108469

Citation

Lahut, Suna, et al. "Blood RNA Biomarkers in Prodromal PARK4 and Rapid Eye Movement Sleep Behavior Disorder Show Role of Complexin 1 Loss for Risk of Parkinson's Disease." Disease Models & Mechanisms, vol. 10, no. 5, 2017, pp. 619-631.
Lahut S, Gispert S, Ömür Ö, et al. Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease. Dis Model Mech. 2017;10(5):619-631.
Lahut, S., Gispert, S., Ömür, Ö., Depboylu, C., Seidel, K., Domínguez-Bautista, J. A., Brehm, N., Tireli, H., Hackmann, K., Pirkevi, C., Leube, B., Ries, V., Reim, K., Brose, N., den Dunnen, W. F., Johnson, M., Wolf, Z., Schindewolf, M., Schrempf, W., ... Auburger, G. (2017). Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease. Disease Models & Mechanisms, 10(5), 619-631. https://doi.org/10.1242/dmm.028035
Lahut S, et al. Blood RNA Biomarkers in Prodromal PARK4 and Rapid Eye Movement Sleep Behavior Disorder Show Role of Complexin 1 Loss for Risk of Parkinson's Disease. Dis Model Mech. 2017 05 1;10(5):619-631. PubMed PMID: 28108469.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease. AU - Lahut,Suna, AU - Gispert,Suzana, AU - Ömür,Özgür, AU - Depboylu,Candan, AU - Seidel,Kay, AU - Domínguez-Bautista,Jorge Antolio, AU - Brehm,Nadine, AU - Tireli,Hülya, AU - Hackmann,Karl, AU - Pirkevi,Caroline, AU - Leube,Barbara, AU - Ries,Vincent, AU - Reim,Kerstin, AU - Brose,Nils, AU - den Dunnen,Wilfred F, AU - Johnson,Madrid, AU - Wolf,Zsuzsanna, AU - Schindewolf,Marc, AU - Schrempf,Wiebke, AU - Reetz,Kathrin, AU - Young,Peter, AU - Vadasz,David, AU - Frangakis,Achilleas S, AU - Schröck,Evelin, AU - Steinmetz,Helmuth, AU - Jendrach,Marina, AU - Rüb,Udo, AU - Başak,Ayşe Nazlı, AU - Oertel,Wolfgang, AU - Auburger,Georg, Y1 - 2017/01/20/ PY - 2016/09/30/received PY - 2017/01/12/accepted PY - 2017/1/22/pubmed PY - 2018/6/21/medline PY - 2017/1/22/entrez KW - Biomarkers KW - Complexin 1 KW - PARK4 KW - Parkinson's disease KW - Rapid eye movement sleep behavior disorder KW - α-synuclein SP - 619 EP - 631 JF - Disease models & mechanisms JO - Dis Model Mech VL - 10 IS - 5 N2 - Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3'-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction. SN - 1754-8411 UR - https://www.unboundmedicine.com/medline/citation/28108469/Blood_RNA_biomarkers_in_prodromal_PARK4_and_rapid_eye_movement_sleep_behavior_disorder_show_role_of_complexin_1_loss_for_risk_of_Parkinson's_disease_ L2 - http://dmm.biologists.org/cgi/pmidlookup?view=long&pmid=28108469 DB - PRIME DP - Unbound Medicine ER -