Blood RNA biomarkers in prodromal PARK4 and apid eye movement sleep behavior disorder show role of complexin-1 loss for risk of Parkinson's disease

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
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.
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Metadaten
Author:Suna Lahut, Suzana Gispert, Özgür Ömür, Candan Depboylu, Kay Seidel, Jorge Antolio Domínguez Bautista, Nadine Brehm, Hülya Tireli, Karl Hackmann, Caroline Pirkevi, Barbara Leube, Vincent Ries, Kerstin Reim, Nils Brose, Wilfred F. A. den Dunnen, Madrid Johnson, Zsuzsanna Wolf, Marc Schindewolf, Wiebke Schrempf, Kathrin Reetz, Peter Young, David Vadasz, Achilleas S. Frangakis, Evelin Schröck, Helmuth Steinmetz, Marina Jendrach, Udo Rüb, Ayşe Nazlı Başak, Wolfgang Oertel, Georg Auburger
URN:urn:nbn:de:hebis:30:3-427551
DOI:http://dx.doi.org/10.1242/dmm.028035
ISSN:1754-8411
ISSN:1754-8403
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=28108469
Parent Title (English):Disease models & mechanisms
Publisher:Company of Biologists Limited
Place of publication:Cambridge
Document Type:Article
Language:English
Date of Publication (online):2017/05/04
Date of first Publication:2017/01/20
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/05/04
Tag:Biomarkers; Complexin 1; PARK4; Parkinson’s disease; Rapid eye movement sleep behavior disorder; α-synuclein
Volume:10
Pagenumber:13
First Page:619
Last Page:631
Note:
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
HeBIS PPN:424820005
Institutes:Biowissenschaften
Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0

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