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

• DOI: 10.1007/s00401-019-02074-0
• Publication Date: 2019-09-18T18:06:51Z
• Authors: Conceição Bettenc...; Sandrine C. Foti; Yasuo Miki; Juan Botia; Aparajita Chatterjee; Thomas T. Warner; Tamas Revesz; Tammaryn Lashley; Robert Balazs; Emmanuelle Viré; Janice L. Holton
• Keywords: Olivopontocerebellar atrophy; Synucleinopathies; C9ORF72

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