Journal Article

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

Schindewolf, Marc, Young, Peter, Wolf, Zsuzsanna, Pirkevi, Caroline, Rüb, Udo, Brehm, Nadine, Johnson, Madrid, Frangakis, Achilleas S., Auburger, Georg, Hackmann, Karl, Domínguez-Bautista, Jorge Antolio, Seidel, Kay, Tireli, Hülya, Ömür, Özgür, Schröck, Evelin, Başak, Ayşe Nazlı, Reim, Kerstin, Gispert, Suzana, Depboylu, Candan, Reetz, Kathrin, Jendrach, Marina, Schrempf, Wiebke, Leube, Barbara, Oertel, Wolfgang, den Dunnen, Wilfred F., Vadasz, David, Steinmetz, Helmuth, Brose, Nils, Lahut, Suna, Ries, Vincent

2017

Overview

Parkinson's disease (PD) is a frequent neurodegenerative process at old age. Accumulation and aggregation of the lipid-binding SNARE complex component alpha-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity are intensely investigated. In view of physiological SNCA roles 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. The expression of other Parkinson's disease gene was not, but complexin-1 (CPLX1) mRNA downregulation was correlated with genotype. In global RNAseq profiling of blood from presymptomatic PARK4, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, toll like receptor signalling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH, and PLTP mRNA upregulations were validated in PARK4. When analysing cases with REM sleep behaviour disorder (RBD), 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 SNP that is significantly associated with PD risk. In summary, our data define CPLX1 as PD risk factor and provide functional insights into the role and regulation of blood alpha-synuclein levels. The novel blood biomarkers of PARK4 in this Turkish family may become useful for PD prediction.