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Methionine sulfoxide reductase regulates brain catechol-O-methyl transferase activity
Moskovitz, Jackob Walss-Bass, Consuelo Cruz, Dianne A. Thompson, Peter M. Bortolato, Marco
Moskovitz, Jackob
Walss-Bass, Consuelo
Cruz, Dianne A.
Thompson, Peter M.
Bortolato, Marco
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Abstract
Catechol-O-methyl transferase (COMT) plays a key role in the degradation of brain dopamine (DA). Specifically,
low COMT activity results in higher DA levels in the prefrontal cortex (PFC), thereby reducing the vulnerability
for attentional and cognitive deficits in both psychotic and healthy individuals. COMT activity is markedly
reduced by a non-synonymous single-nucleotide polymorphism (SNP) that generates a valine-to-methionine
substitution on the residue 108/158, by means of as-yet incompletely understood post-translational mechanisms.
One post-translational modification is methionine sulfoxide, which can be reduced by the methionine sulfoxide
reductase (Msr) A and B enzymes. We used recombinant COMT proteins (Val/Met108) and mice (wild-type (WT)
and MsrA knockout) to determine the effect of methionine oxidation on COMT activity and COMT interaction
with Msr, through a combination of enzymatic activity and Western blot assays. Recombinant COMT activity is
positively regulated by MsrA, especially under oxidative conditions, whereas brains of MsrA knockout mice
exhibited lower COMT activity (as compared with their WT counterparts). These results suggest that COMT activity
may be reduced by methionine oxidation, and point to Msr as a key molecular determinant for the modulation
of COMT activity in the brain. The role of Msr in modulating cognitive functions in healthy individuals
and schizophrenia patients is yet to be determined.
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This is the published version. Copyright 2014 Oxford University Press
Date
2014-10-01
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Oxford University Press
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Keywords
Catechol-O-methyltransferase, Methionine oxidation, Oxidative stress, Post-translation modification, Prefrontal cortex
Citation
Moskovitz, Jackob, Consuelo Walss-Bass, Dianne A. Cruz, Peter M. Thompson, and Marco Bortolato. "Methionine Sulfoxide Reductase Regulates Brain Catechol-O-methyl Transferase Activity." The International Journal of Neuropsychopharmacology Int. J. Neuropsychopharm. 17.10 (2014): 1707-713. http://dx.doi.org/10.1017/S1461145714000467