# Global DNA methylation is not elevated in blood samples from Machado-Joseph disease mutation carriers

## TL;DR

This study found no increase in global DNA methylation in blood samples from individuals carrying the Machado-Joseph disease mutation.

## Contribution

The study provides new evidence that global DNA methylation is not elevated in Machado-Joseph disease mutation carriers.

## Key findings

- No differences in global 5-mC levels were found between MJD carriers and healthy controls.
- Methylation levels did not correlate with clinical or genetic variables in MJD subjects.
- No changes in global 5-mC levels were observed over time in a follow-up analysis.

## Abstract

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia (SCA) caused by a polyglutamine expansion in the ataxin-3 protein, which initiates a cascade of pathogenic events, including transcriptional dysregulation. Genotype-phenotype correlations in MJD are incomplete, suggesting an influence of additional factors, such as epigenetic modifications, underlying the MJD pathogenesis. DNA methylation is known to impact the pathophysiology of neurodegenerative disorders through gene expression regulation and increased methylation has been reported for other SCAs. In this work we aimed to analyse global methylation in MJD carriers. Global 5-mC levels were quantified in blood samples of 33 MJD mutation carriers (patients and preclinical subjects) and 33 healthy controls, matched by age, sex, and smoking status. For a subset of 16 MJD subjects, a pilot follow-up analysis with two time points was also conducted. No differences were found in median global 5-mC levels between MJD mutation carriers and controls and no correlations between methylation levels and clinical or genetic variables were detected. Also, no alterations in global 5-mC levels were observed over time. Our findings do not support an increase in global blood methylation levels associated with MJD.