title: 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.
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 withSNCAgene 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. StrongSPP1,GZMHandPLTPmRNA 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 bloodCPLX1levels were altered. Validation experiments confirmed an inverse mutual regulation ofSNCAandCPLX1mRNA levels. In the 3'-UTR of theCPLX1gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data defineCPLX1as 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.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.|NDAL, Boğaziçi University, Istanbul 34342, Turkey.
authors.forename: Suna
authors.identifier: 0000-0003-3320-6825
authors.initials: S
authors.lastname: Lahut
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.|NDAL, Boğaziçi University, Istanbul 34342, Turkey.
authors.forename: Özgür
authors.initials: Ö
authors.lastname: Ömür
authors.affiliation: Department of Neurology, Philipps University, Baldingerstrasse, Marburg 35043, Germany.
authors.forename: Candan
authors.initials: C
authors.lastname: Depboylu
authors.affiliation: Dr Senckenberg Chronomedical Institute, Goethe University, Frankfurt/Main 60590, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Seidel
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.
authors.forename: Jorge Antolio
authors.initials: JA
authors.lastname: Domínguez-Bautista
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Brehm
authors.affiliation: Department of Neurology, Haydarpaşa Numune Training and Research Hospital, Istanbul 34668, Turkey.
authors.forename: Hülya
authors.identifier: 0000-0002-1830-514X
authors.initials: H
authors.lastname: Tireli
authors.affiliation: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, Dresden 01307, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.affiliation: NDAL, Boğaziçi University, Istanbul 34342, Turkey.
authors.forename: Caroline
authors.identifier: 0000-0002-7958-631X
authors.initials: C
authors.lastname: Pirkevi
authors.affiliation: Institute of Human Genetics, Heinrich Heine University, Düsseldorf 40225, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Leube
authors.affiliation: Department of Neurology, Philipps University, Baldingerstrasse, Marburg 35043, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ries
authors.affiliation: Department of Molecular Neurobiology and Center for the Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, Göttingen 37075, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Reim
authors.affiliation: Department of Molecular Neurobiology and Center for the Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, Göttingen 37075, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.affiliation: Department of Pathology and Medical Biology, Medical Center, University, Groningen 9700 RB, The Netherlands.
authors.forename: Wilfred F
authors.initials: WF
authors.lastname: den Dunnen
authors.affiliation: Buchmann Institute for Molecular Life Sciences and Institute for Biophysics, Goethe University, Frankfurt/Main 60438, Germany.
authors.forename: Madrid
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Haemophilia Centre, Medical Clinic III, Institute of Immunohaematology and Transfusion Medicine, Goethe University, Frankfurt/Main 60590, Germany.
authors.forename: Zsuzsanna
authors.identifier: 0000-0003-2682-7340
authors.initials: Z
authors.lastname: Wolf
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine and Hemostaseology, Goethe University, Frankfurt 60590, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schindewolf
authors.affiliation: Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität, Dresden 01307, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Schrempf
authors.affiliation: Department of Neurology, RWTH Aachen University Hospital, Aachen 52074, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Reetz
authors.affiliation: Department of Sleep Medicine and Neuromuscular Disorders, University Hospital Münster, Münster 48149, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.affiliation: Department of Neurology, Philipps University, Baldingerstrasse, Marburg 35043, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Vadasz
authors.affiliation: Buchmann Institute for Molecular Life Sciences and Institute for Biophysics, Goethe University, Frankfurt/Main 60438, Germany.
authors.forename: Achilleas S
authors.initials: AS
authors.lastname: Frangakis
authors.affiliation: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, Dresden 01307, Germany.
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.
authors.forename: Helmuth
authors.initials: H
authors.lastname: Steinmetz
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Jendrach
authors.affiliation: Dr Senckenberg Chronomedical Institute, Goethe University, Frankfurt/Main 60590, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
authors.affiliation: NDAL, Boğaziçi University, Istanbul 34342, Turkey.
authors.forename: Ayşe Nazlı
authors.initials: AN
authors.lastname: Başak
authors.affiliation: Department of Neurology, Philipps University, Baldingerstrasse, Marburg 35043, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Oertel
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt/Main 60590, Germany auburger@em.uni-frankfurt.de.
authors.forename: Georg
authors.identifier: 0000-0001-7355-2701
authors.initials: G
authors.lastname: Auburger
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D015415:Biomarkers / Q000097:blood*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D020961:Lewy Body Disease / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000097:blood / Q000235:genetics*; D020187:REM Sleep Behavior Disorder / Q000097:blood* / Q000503:physiopathology; D012313:RNA / Q000097:blood*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051844:alpha-Synuclein / Q000097:blood / Q000172:deficiency* / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015415:Biomarkers; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051844:alpha-Synuclein; C095992:complexin I; D012313:RNA
keywords: Biomarkers; Complexin 1; PARK4; Parkinson's disease; Rapid eye movement sleep behavior disorder; α-synuclein