White matter DNA methylation profiling reveals deregulation of HIP1, LMAN2, MOBP, and other loci in multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a fatal late-onset neurodegenerative disease. Although presenting with distinct pathological hallmarks, which in MSA consist of glial cytoplasmic inclusions (GCIs) containing fibrillar α-synuclein in oligodendrocytes, both MSA and Parkinson's disease are α-synucleinopathies. Pathologically, MSA can be categorized into striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) or mixed subtypes. Despite extensive research, the regional vulnerability of the brain to MSA pathology remains poorly understood. Genetic, epigenetic and environmental factors have been proposed to explain which brain regions are affected by MSA, and to what extent. Here, we explored for the first time epigenetic changes in post-mortem brain tissue from MSA cases. We conducted a case-control study, and profiled DNA methylation in white mater from three brain regions characterized by severe-to-mild GCIs burden in the MSA mixed subtype (cerebellum, frontal lobe and occipital lobe). Our genome-wide approach using Illumina MethylationEPIC arrays and a powerful cross-region analysis identified 157 CpG sites and 79 genomic regions where DNA methylation was significantly altered in the MSA mixed-subtype cases. HIP1, LMAN2 and MOBP were amongst the most differentially methylated loci. We replicated these findings in an independent cohort and further demonstrated that DNA methylation profiles were perturbed in MSA mixed subtype, and also to variable degrees in the other pathological subtypes (OPCA and SND). Finally, our comethylation network analysis revealed several molecular signatures (modules) significantly associated with MSA (disease status and pathological subtypes), and with neurodegeneration in the cerebellum. Importantly, the co-methylation module having the strongest association with MSA included a CpG in SNCA, the gene encoding α-synuclein. Altogether, our results provide the first evidence for DNA methylation changes contributing to the molecular processes altered in MSA, some of which are shared with other neurodegenerative diseases, and highlight potential novel routes for diagnosis and therapeutic interventions.

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

“…The functions of these genes are related to the extracellular matrix (COL23A1, LTBP3) and the immune system (PTPRN2, CYFIP1) while TIMP2 falls in both these categories. Furthermore, we investigated total methylation levels in order to compare our results directly to the study by Bettencourt et al [8]. Specifically, Bettencourt et al highlights probes on HIP1, LMAN2, and MOBP genes, however, in our setup the most significant probes on HIP1 and LMAN2 genes were only nominally significant (cg08710628 on HIP1, P = 0.003; cg05408837 on LMAN2, P = 0.008), whereas no probes on MOBP were significant.…”

“…In order to perspective our results to other EWAS studies on brain tissue from neurodegenerative diseases, we investigated overlaps for our probes with an adj. P < 0.20 and four other studies: one MSA study [8], one PSP study [13], and two AD studies [10,34]. In total, we investigated 2181 unique probes and 1239 unique genes from these studies.…”

“…Other mechanisms such as epigenetic changes may better explain development of MSA as they are proposed to causally reflect genetic-environmental interactions [6]. Epigenetic changes to the DNA have long been suspected to play a role in neurodegenerative diseases, including MSA [7,8], but also Alzheimer's disease (AD) [9,10], Parkinson's disease (PD) [11,12], and Progressive Supranuclear Palsy (PSP) [13]. Specifically, 5-methylcytosine (5mC) is recognized as an important regulator of gene expression [14], but is not the only DNA-based epigenetic modification.…”

“…Disease-specific differences in global 5mC and 5hmC levels have been reported in selected areas of the brain in MSA patients by immunodetection [19]. However, the region-specific differences in global 5mC methylation levels could not be replicated in a recent array-based study as analysis of 5hmC was not performed [8]. Therefore, more information on the epigenetic landscape in MSA is required in order to infer on fundamental biological functions involved.…”

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

“…Recently, epigenetic modifications, such as DNA methylation changes, have also been identified in neurodegenerative diseases. A recent study reported white matter tissue DNA methylation changes associated with MSA, including changes in HIP1, LMAN2 and MOBP [8].…”