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Oxidative stress can cause methionine oxidation that has been implicated in various proteins malfunctions, if not adequately reduced by the methionine sulfoxide reductase system. Recent evidence has found oxidized methionine residues in neurodegenerative conditions. Previously, we have described elevated levels of brain pathologies and an abnormal walking pattern in the methionine sulfoxide reductase A knockout (MsrA(-/-)) mouse. Here we show that MsrA(-/-) mice have compromised complex task learning capabilities relative to wild-type mice. Likewise, MsrA(-/-) mice exhibit lower locomotor activity and altered gait that exacerbated with age. Furthermore, MsrA(-/-) mice were less responsive to amphetamine treatment. Consequently, brain dopamine levels were determined. Surprisingly, relative to wild-type mice, MsrA(-/-) brains contained significantly higher levels of dopamine up to 12 months of age, while lower levels of dopamine were observed at 16 months of age. Moreover, striatal regions of MsrA(-/-) mice showed an increase of dopamine release parallel to observed dopamine levels. Similarly, the expression pattern of tyrosine hydroxylase activating protein correlated with the age-dependent dopamine levels. Thus, it is suggested that dopamine regulation and signaling pathways are impaired in MsrA(-/-) mice, which may contribute to their abnormal behavior. These observations may be relevant to age-related neurological diseases associated with oxidative stress.

Previously we have shown that the binding complex formation of methionine sulfoxide reductase A (msrA) promoter and calcium phospholipid binding protein (CPBP) enhances msrA transcription and expression. The msrA promoter-CPBP-binding complex (PmsrA-CPBP) formation was similar in Deltatrx1, Deltatrx2, and Deltatrx3 yeast strains and their control, with or without exposure to H(2)O(2). In Deltatrx1/Deltatrx2 double mutant the PmsrA-CPBP was similar to its parent strain, following exposure to H(2)O(2) for 30 min. However, a late-onset loss of PmsrA-CPBP binding activity occurred following exposure to H(2)O(2) for 24 hours. Hence, it was inferred that both Trx1 and Trx2 are involved in the PmsrA-CPBP formation during prolonged oxidative stress conditions. In addition, the survival rate of the Deltatrx1Delta/trx2 double mutant was approximately 10% of its parent strain when exposed to H(2)O(2.) The MsrA activity was obliterated in Deltatrx1/Deltatrx2 and Deltatrx1 strains and remained intact in the Deltatrx2 and Deltatrx3 strains. The msrA mRNA level in Deltatrx1 was significantly reduced in comparison to that of its control, slightly reduced in Deltatrx2, and unchanged in Deltatrx3, respectively. It is suggested that under normal growth conditions Trx1 is essential for msrA transcription and activity. Moreover, following long-term oxidative stress conditions, Trx1 and Trx2 appear to promote PmsrA-CPBP-binding activity and cell survival.