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To the Editors, Multiple system atrophy (MSA) is a fatal neurodegenerative disease and its aetiology remains elusive. The pathological hallmark of MSA is the presence of glial cytoplasmic inclusions (GCIs) containing fibrillar αsynuclein in oligodendrocytes [3, 6], but the regional vulnerability of the brain to these GCIs remains poorly understood. We read with interest the paper by Rydbirk and colleagues recently published in Acta Neuropathologica Communications [5]. They investigated DNA methylation (5mC) and hydroxymethylation (5hmC) changes in prefrontal cortex samples from MSA patients. We reported previously [1] total DNA methylation (5mC + 5hmC) changes in MSA, and this work by Rydbirk et al. [5] further supports a contribution of epigenetic factors, namely DNA methylation, to MSA brain pathophysiology. Given the differentially methylated CpGs (e.g. in AREL1 and KTN1), regions (DMRs) and blocks reported for the 5mC fraction by Rydbirk and colleagues [5], we performed additional loci-specific analysis of our MSA DNA methylation data [1]. We used data from our discovery cohort [1], which was composed of neuropathologically confirmed MSA mixed cases and controls, and investigated multiple brain regions characterized by different degrees of GCI burden in MSA, including the cerebellum, and the frontal and occipital lobes. In the frontal lobe, no changes were detected in AREL1 nor in the reported intergenic CpGs (Supplementary Table S1.1). Although with small effects (absolute delta betas < 5%), two CpGs in KTN1 were nominally significant (cg14002714 and cg21059882; p < 0.05). Regarding the block covering PHF3, two CpGs were nominally significant (cg16049132 and cg10435600; p < 0.05). Additionally, 52 CpGs in the DMR genes were nominally significant in our data, 14 of which (in 5 genes: FUT4, BCAR1, CTSZ, ZIC4 and FERMT3) demonstrated absolute delta betas of ≥5%. With the exception of cg18023065 in FUT4, none of these changes passed multiple testing correction (p < 9.07 × 10 5 [0.05/551 CpGs]). Some of those CpGs and additional CpGs were also nominally significant in the other brain regions

Epigenomics and transcriptomics analyses of multiple system atrophy brain tissue supports a role for inflammatory processes in disease pathogenesis