Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients

Rasmus Rydbirk,Jonas Folke,Anne-Mette Hejl,Bente Pakkenberg,Morten Blaabjerg,Annemette Løkkegaard,Jorg Tost,Florence Busato,Elodie Roché,Susana Aznar,Mette Møller,Erik Hvid Danielsen,Matthias Bode,Tomasz Brudek,Alisha Shahzad Chauhan

doi:10.1186/s40478-020-00908-7

Abstract

Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known about the molecular processes underlying disease development. Its clinical overlap with related neurodegenerative movement disorders underlines the importance for expanding the knowledge of pathological brain processes in MSA patients to improve distinction from similar diseases. In the current study, we investigated DNA methylation changes in brain samples from 41 MSA patients and 37 healthy controls. We focused on the prefrontal cortex, a moderately affected area in MSA. Using Illumina MethylationEPIC arrays, we investigated 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC) changes throughout the genome. We identified five significantly different 5mC probes (adj. P < 0.05), of which one probe mapping to the AREL1 gene involved in antigen presentation was decreased in MSA patients. This decrease correlated with increased 5hmC levels. Further, we identified functional DNA methylation modules involved in inflammatory processes. As expected, the decreased 5mC levels on AREL1 was concordant with increased gene expression levels of both AREL1 as well as MHC Class I HLA genes in MSA brains. We also investigated whether these changes in antigen-related processes in the brain associated with changes in peripheral mononuclear cells. Using flow cytometry on an independent cohort of MSA patients, we identified a decrease in circulating non-classical CD14+CD16++ blood monocytes, whereas T and NK cell populations were unchanged. Taken together, our results support the view of an active neuroimmune response in brains of MSA patients.

Highlights

Multiple System Atrophy (MSA) is a detrimental disease with no treatment possibilities
We found the fraction of non-classical CD14+CD16++ monocytes to be decreased in MSA patients, whereas no differences were observed for the T cell or NK cell fractions
We identified methylation changes in the prefrontal cortex of MSA patients, larger effects may be found in other brain region as demonstrated by Bettencourt et al a recent study screened for epigenetic changes in different brain areas in Parkinson’s disease (PD) and MSA patients which showed a global increase of 5hmC intensity in the white matter of the cerebellum in both PD and MSA patients [19], while no difference in methylation levels was observed in the neocortex between PD patients and controls

Summary

Introduction

Multiple System Atrophy (MSA) is a detrimental disease with no treatment possibilities. It is a neurodegenerative disease of the alpha-synucleinopathies where alphasynuclein accumulates in both neurons and oligodendrocytes of the brain as neuronal or glial cytoplasmic inclusions, respectively [1, 2]. The involvement of genomic factors in MSA development has been investigated [4], but so far the results have been inconclusive. This may correlate well with an estimated heritability of MSA below 7% [5]. Disease-specific differences in global 5mC and 5hmC levels have been reported in selected areas of the brain in MSA patients by immunodetection [19]. More information on the epigenetic landscape in MSA is required in order to infer on fundamental biological functions involved

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