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Updated: Jan 19, 2026
The Detection of 5-Hydroxymethylcytosine in Neural Stem Cells and Brains of Mice
Published on: September 19, 2019
White matter DNA methylation profiling reveals deregulation of HIP1, LMAN2, MOBP, and other loci in multiple system
Conceição Bettencourt1,2, Sandrine C Foti3,4, Yasuo Miki3,5
1The Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK. c.bettencourt@ucl.ac.uk.
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 co-methylation 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.
Insights
Epigenetic changes, specifically DNA methylation, are altered in Multiple System Atrophy (MSA), a neurodegenerative disease. These DNA methylation changes are linked to MSA subtypes and may offer new diagnostic and therapeutic targets.
Area of Science:
- Neuroscience
- Epigenetics
- Neurodegenerative Diseases
Background:
- Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by glial cytoplasmic inclusions (GCIs) of alpha-synuclein.
- MSA shares alpha-synuclein pathology with Parkinson's disease, but exhibits distinct regional vulnerability.
- Understanding the epigenetic factors influencing brain region vulnerability in MSA is crucial.
Purpose of the Study:
- To investigate DNA methylation changes in post-mortem brain tissue from patients with MSA.
- To identify specific genomic regions and genes affected by altered DNA methylation in different MSA subtypes.
- To explore the association of DNA methylation patterns with MSA and neurodegeneration.
Main Methods:
- A case-control study was conducted using post-mortem white matter from cerebellum, frontal, and occipital lobes of MSA patients and controls.
- Genome-wide DNA methylation profiling was performed using Illumina MethylationEPIC arrays.
- Co-methylation network analysis was employed to identify molecular signatures associated with MSA and neurodegeneration.
Main Results:
- Significant alterations in DNA methylation were identified at 157 CpG sites and 79 genomic regions in MSA mixed-subtype cases.
- Genes such as HIP1, LMAN2, and MOBP showed differential methylation, findings replicated in an independent cohort.
- Co-methylation network analysis revealed modules significantly associated with MSA status, subtypes, and cerebellar neurodegeneration, including a CpG site in SNCA.
Conclusions:
- This study provides the first evidence of DNA methylation alterations contributing to molecular processes in MSA.
- Identified DNA methylation changes may be shared with other neurodegenerative diseases.
- These findings highlight potential novel avenues for MSA diagnosis and therapeutic interventions.
