Plasma cfDNA hypermethylation at SNCA intron 1 as a potential blood-based epigenetic signal in Parkinson's disease and multiple system atrophy.

BACKGROUND

The accumulation of α-synuclein (SNCA) in the central nervous system is a hallmark of Parkinson's disease (PD) and multiple system atrophy (MSA). SNCA intron 1 methylation is implicated in SNCA transcriptional regulation and may serve as a peripheral epigenetic signal in synucleinopathies. However, studies of SNCA methylation in leukocyte-derived DNA have yielded inconsistent results. We aimed to evaluate whether cell-free DNA (cfDNA)-based SNCA intron 1 methylation differs in PD or MSA compared with normal controls (NC).

METHODS

Plasma cfDNA was collected from 105 patients with PD, 50 with MSA, and 114 NC. DNA methylation at CpG sites 10-17 was quantified by bisulfite pyrosequencing. Multivariable linear and logistic regression models, adjusted for age, sex, and education, were used to compare methylation levels and estimate odds ratios (ORs).

RESULTS

Patients with PD exhibited hypermethylation at CpG site 14 and higher mean methylation across CpG sites 10-17 compared with NC. Patients with MSA showed hypermethylation at CpG sites 10, 12, 13, and 17 and elevated mean methylation. Elevated mean methylation was also observed in drug-naïve de novo PD and early-stage PD patients. Compared with the lowest tertile, the highest mean methylation tertile was associated with increased odds of PD (OR, 2.49; 95% CI, 1.08-5.92) and MSA (OR, 5.02; 95% CI, 1.58-18.00).

CONCLUSION

Plasma cfDNA SNCA intron 1 hypermethylation is associated with PD and MSA and detectable in drug-naïve and early-stage PD. It may represent a peripheral epigenetic alteration and warrants evaluation as an adjunctive signal for early screening.