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Reduced S-adenosylmethionine:protein-lysine N-methyltransferase activity (protein methylase III) in shiverer mutant
Abstract:
Mice with the dysmyelinating mutation shiverer were studied by measuring the activity of two protein methylases and myelin marker enzymes in the brain. It was observed that S-adenosylmethionine:protein-lysine N-methyltransferase (protein methylase III, EC. 2.1.1.43) activity is significantly reduced in phenotypically affected homozygous shiverer (shi/shi) mutant mouse brain compared to the unaffected heterozygous littermate brain. This reduction in enzyme activity is manifested mainly by reduced formation of trimethyllysine during the in vitro methylation of histone. In contrast, myelin marker enzymes such as 2',3'-cyclic nucleotide 3'-phosphohydrolase and 5'-nucleotidase as well as S-adenosyl-methionine:protein-carboxyl O-methyltransferase (protein methylase II, EC. 2.1.1.24) activities were not significantly affected in these strains of mice.
Insights
The enzyme S-adenosylmethionine:protein-lysine N-methyltransferase (protein methylase III) activity is significantly reduced in the brains of shiverer mutant mice. This protein methylase III reduction impacts histone methylation, a key process in myelin development.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- The shiverer (shi) mouse model exhibits a spontaneous mutation leading to dysmyelination.
- Understanding the molecular mechanisms underlying dysmyelination is crucial for neurological research.
Purpose of the Study:
- To investigate the activity of specific protein methylases and myelin marker enzymes in the shiverer mouse brain.
- To determine the role of S-adenosylmethionine:protein-lysine N-methyltransferase (protein methylase III) in the shiverer mutation.
Main Methods:
- Enzyme activity assays were performed on brain tissue from homozygous shiverer (shi/shi) mutant mice and unaffected heterozygous littermates.
- Quantification of S-adenosylmethionine:protein-lysine N-methyltransferase (protein methylase III) and S-adenosylmethionine:protein-carboxyl O-methyltransferase (protein methylase II) activities.
- Measurement of myelin marker enzymes: 2',3'-cyclic nucleotide 3'-phosphohydrolase and 5'-nucleotidase.
Main Results:
- Significantly reduced S-adenosylmethionine:protein-lysine N-methyltransferase (protein methylase III) activity was observed in shi/shi mouse brains compared to controls.
- The reduced activity of protein methylase III correlated with decreased trimethyllysine formation during in vitro histone methylation.
- Activities of protein methylase II and myelin marker enzymes (2',3'-cyclic nucleotide 3'-phosphohydrolase, 5'-nucleotidase) remained unaffected.
Conclusions:
- The study identifies a significant deficit in S-adenosylmethionine:protein-lysine N-methyltransferase (protein methylase III) activity in the shiverer mouse model.
- This deficiency in protein methylase III likely contributes to the dysmyelination phenotype observed in shiverer mice.
- Protein methylase III, not protein methylase II or other myelin markers, is specifically implicated in the shiverer mutation's pathology.