TY  - JOUR
A1  - Lahut, Suna
A1  - Gispert, Suzana
A1  - Ömür, Özgür
A1  - Depboylu, Candan
A1  - Seidel, Kay
A1  - Domínguez Bautista, Jorge Antolio
A1  - Brehm, Nadine
A1  - Tireli, Hülya
A1  - Hackmann, Karl
A1  - Pirkevi, Caroline
A1  - Leube, Barbara
A1  - Ries, Vincent
A1  - Reim, Kerstin
A1  - Brose, Nils
A1  - Dunnen, Wilfred F. A. den
A1  - Johnson, Madrid
A1  - Wolf, Zsuzsanna
A1  - Schindewolf, Marc
A1  - Schrempf, Wiebke
A1  - Reetz, Kathrin
A1  - Young, Peter
A1  - Vadasz, David
A1  - Frangakis, Achilleas S.
A1  - Schröck, Evelin
A1  - Steinmetz, Helmuth
A1  - Jendrach, Marina
A1  - Rüb, Udo
A1  - Başak, Ayşe Nazlı
A1  - Oertel, Wolfgang H.
A1  - Auburger, Georg
T1  - 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
T2  - Disease models & mechanisms
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.
KW  - α-synuclein
KW  - Complexin 1
KW  - PARK4
KW  - Rapid eye movement sleep behavior disorder
KW  - Parkinson’s disease
KW  - Biomarkers
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/42755
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-427551
SN  - 1754-8411
SN  - 1754-8403
N1  - 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.
VL  - 10
SP  - 619
EP  - 631
PB  - Company of Biologists Limited
CY  - Cambridge
ER  -