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Peptidylarginine deiminase activity in postmortem white matter of patients with multiple sclerosis
J De Keyser1, M Schaaf, A Teelken
1Department of Neurology, Academisch Ziekenhuis Groningen, The Netherlands. j.h.a.de.keyser@neuro.azg.nl
Abstract:
The myelin sheath in multiple sclerosis (MS) appears to contain a higher proportion of the citrullinated isoform of myelin basic protein MBP-C8. In vitro, MBP-associated arginine is deiminated to citrulline by the enzyme peptidylarginine deiminase (PAD). We investigated PAD activity in white matter from postmortem human brain samples by measuring the formation of citrulline from benzoylarginine ethyl esther. PAD activity in MS white matter was not different from that in controls. In neonates, in whom MBP is exclusively of the C8 type, white matter PAD activity was not different from that in adults. Our results suggest that in human brain either PAD plays no role in the formation of MBP-C8, or there may be a better accessibility of MBP in myelin in neonates and MS to the enzyme.
Insights
Multiple Sclerosis (MS) brain tissue shows increased citrullinated myelin basic protein (MBP-C8). However, peptidylarginine deiminase (PAD) enzyme activity was similar in MS and control brains, suggesting limited role in MBP-C8 formation in MS.
Area of Science:
- Neuroscience
- Biochemistry
- Immunology
Background:
- Multiple Sclerosis (MS) is a demyelinating disease characterized by increased citrullinated myelin basic protein (MBP-C8).
- Peptidylarginine deiminase (PAD) enzymes catalyze the deimination of arginine to citrulline, a key post-translational modification.
- The role of PAD activity in MBP citrullination within the human brain, particularly in MS, remains unclear.
Purpose of the Study:
- To investigate peptidylarginine deiminase (PAD) activity in human brain white matter from postmortem samples.
- To compare PAD activity between individuals with Multiple Sclerosis (MS) and healthy controls.
- To assess PAD activity in relation to myelin basic protein (MBP) citrullination.
Main Methods:
- Postmortem human brain white matter samples were obtained from MS patients and controls.
- PAD activity was measured in vitro using benzoylarginine ethyl ester as a substrate.
- Citrulline formation was quantified to determine enzymatic activity.
Main Results:
- PAD activity in white matter of MS brains was not significantly different from that of control brains.
- PAD activity in neonatal white matter, where MBP is exclusively the C8 isoform, was comparable to adult white matter.
- No correlation was found between PAD activity levels and the presence of MS.
Conclusions:
- The study suggests that PAD may play a limited or no direct role in the formation of citrullinated myelin basic protein (MBP-C8) in the human brain.
- Alternatively, differences in MBP accessibility within the myelin sheath in MS or during development might influence citrullination.
- Further research is needed to elucidate the mechanisms regulating MBP citrullination in neurological conditions like MS.