SNCA methylation and PD progression (in PD, UKB)
NeuroMMSig synuclein subgraph:
Alpha Synuclein (SNCA) is a key component of Lewy-bodies found in Parkinson’s disease (PD) patients and several studies suggest, that the SCNA gene harbours significant risk haplotypes for sporadic PD.1 Point mutations in the SCNA gene and multiplication of wildtype SCNA cause familiar parkinsonian syndromes with high penetrance.
Comprehensive promoter analyses and recent studies of SCNA mRNA levels strengthened the hypothesis that genotype dependent regulatory mechanisms could contribute to increased expression of SCNA in PD.
We have shown that DNA - methylation modulates the expression of SCNA and hypothesize that differential methylation of SNCA could identifiy PD patients and may set apart subgroups of patients. The role of differential methylation of SNCA in AD has not been explored yet. But the measurements of methylation in pb DNA showed how L-DOPA can influence this process:
Five genes, GSTT1, MRI1, KCNH1, TMEM9, and TUBA3E, were reported to be significantly hypermethylated resulting in low expression of genes. However, there were no studies describing the functional role of these genes in the PD context. In case of acetylation modification, H3F3A, HIST3H3, and HIST4H4 were shown to be acetylated under disease conditions. Acetylated H3F3A increases CASP3 activity and thereby may cause cell damage. Acetylation in HIST3H3 decreases the expression of SNCA leading to neurotoxicity, whereas HIST4H4 acetylation induces the activity of PRKCD, which promotes apoptotic cell death. Phosphorylation of MAPT, SNCA, and PRRX2 causes deposition of neurofibrillary tangles, alpha-synuclein oligomerization, and oxidative stress, respectively, in PD.
NeuroMMSig metabolic, transport related and cytoskeleton subgraph:
Cartoon of the candidate mechanism: