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

AbstractMultiple 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 M SA 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–c ontrol 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 i dentified 157 CpG sites and 79 genomic regions where DNA methylation was significantly altered in the MSA mixed-subtype cases.HIP1,LMAN2 andMOBP 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 degre...
Source: Acta Neuropathologica - Category: Neurology Source Type: research