Blood RNA biomarkers in prodromal PARK4 and REM 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 with <i>SNCA</i> gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (<i>CPLX1</i>) 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 <i>SPP1</i>, <i>GZMH</i> and <i>PLTP</i> 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 <i>CPLX1</i> levels were altered. Validation experiments confirmed an inverse mutual regulation of <i>SNCA</i> and <i>CPLX1</i> mRNA levels. In the 3'-UTR of the <i>CPLX1</i> gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define <i>CPLX1</i> 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.