Parkinson's disease in a large Turkish pedigree with SNCA duplication (PARK4): Developing molecular biomarkers for predictive diagnosis

Accumulation and aggregation of alpha-synuclein (SNCA) is a hallmark of Parkinson's disease (PD). Considering the roles of SNCA in both idiopathic and familial PD, we studied blood samples from a large pedigree with SNCA duplication (PARK4), to identify effects of SNCA gain-of-function on expression levels of downstream genes as potential disease biomarkers. Downregulation of complexin-1 (CPLX1) expression level was found to be correlated with PARK4 and also the further investigated cohort with REM sleep behavior disorder (RBD), which resembles presymptomatic PD. In global RNAseq profiling of blood from presymptomatic PARK4, significant upregulations for immune system, lysosome, lipid and platelet activation pathways were detected. The representative genes of upregulated pathways, SPP1, GZMH, and PLTP, were validated in PARK4. However, unlike CPLX1, they failed to distinguish presymptomatic PD from healthy individuals. The longest size variant (allele 2) of the Rep1 repeat region of the SNCA promoter is known to be associated with PD risk. This region was analyzed in idiopathic PD and restless leg syndrome (RLS). Rep1 allele 2 frequency was found significantly decreased in RLS, suggesting reduced SNCA levels contributing to disease. The WW Domain Containing E3 Ubiquitin Protein Ligase (WWP2) mRNA expression level was tested in PARK4 and RBD and was observed to mimic SNCA expression profiles in both cohorts. Western blot analyses of double transfected cells suggested that in the presence of WWP2, SNCA-wildtype, but not SNCA-A53T-mutant, to be degraded.