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Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated
Fabrizio G Mastronardi1, Abdul Noor, D Denise Wood
1Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada. fabrizio@sickkids.ca
Abstract:
In previous studies, we documented increased citrullinated myelin basic protein (MBP) was present in MBP isolated from multiple sclerosis (MS) normal appearing white matter (NAWM). This increase was due to the myelin enzyme peptidyl argininedeiminase 2 (PAD2). In this study, we show that methylation of cytosine of the PAD2 promoter in DNA from MS NAWM was decreased to one-third of the level of that in DNA from normal white matter. The PAD2 promoter in DNA from thymus obtained from the same MS patients and white matter DNA from Alzheimer's, Huntington's, and Parkinson's was not hypomethylated. DNA demethylase activity in supernatants prepared from NAWM of MS patients was 2-fold higher than the DNA demethylase from normal, Alzheimer's, Huntington's and Parkinson's disease white matter. The amount of PAD2 enzyme and citrullinated MBP was increased in MS NAWM. The decreased methylation of cytosines in the PAD2 promoter may explain the increased synthesis of PAD2 protein that is responsible for the increased amount of citrullinated MBP, which in turn results in loss of myelin stability in MS brain.
Insights
Multiple Sclerosis (MS) involves increased citrullinated myelin basic protein (MBP) due to peptidyl argininedeiminase 2 (PAD2). This study links lower PAD2 promoter methylation and higher DNA demethylase activity in MS white matter to myelin instability.
Area of Science:
- Neuroscience
- Molecular Biology
- Epigenetics
Background:
- Previous studies identified increased citrullinated myelin basic protein (MBP) in multiple sclerosis (MS) normal-appearing white matter (NAWM).
- This citrullination was attributed to the myelin enzyme peptidyl argininedeiminase 2 (PAD2).
Purpose of the Study:
- To investigate the epigenetic mechanisms regulating PAD2 expression in MS NAWM.
- To determine if DNA methylation changes in the PAD2 promoter correlate with increased PAD2 and citrullinated MBP in MS.
Main Methods:
- Quantification of PAD2 promoter methylation in DNA from MS NAWM and control white matter.
- Assay of DNA demethylase activity in MS and control brain tissue.
- Measurement of PAD2 enzyme and citrullinated MBP levels in MS NAWM.
Main Results:
- PAD2 promoter cytosine methylation was significantly decreased (one-third) in MS NAWM compared to normal white matter.
- DNA demethylase activity was 2-fold higher in MS NAWM supernatants.
- Increased PAD2 enzyme and citrullinated MBP levels were observed in MS NAWM.
Conclusions:
- Decreased PAD2 promoter methylation in MS NAWM is linked to increased PAD2 synthesis.
- Elevated PAD2 leads to higher citrullinated MBP, potentially causing myelin instability in MS.
- Epigenetic dysregulation of PAD2 may be a key factor in MS pathogenesis.
