Methionine Sulfoxide Reductase System in Health and Disease

cell cultures has been shown to protect these cells from enhanced MetO accumulations while increasing their survival rates under oxidative stress conditions [24]. In addition, several compounds have demonstrated an ability to induce Msr activity in neuronal cell cultures [25]. This observation supports the identification and development of novel compounds that may serve as therapy treatments against neurodegenerative diseases. Another possible approach to reduce the toxic effects of accumulated MetO-proteins is by enhancing their clearance from an organism. Supportive evidence for the importance of the Msr system in protein degradation is demonstrated by the fact that lack of MsrA contributes to the resistant of proteins to degradation. This phenomenon may be explained by the possible interference of MetO residues to phosphorylation-linked degradation processes. For example, over expression of α-synuclein in msrAnull mutant yeast cells inhibits its phosphorylation and degradation in comparison with wild-type (WT) yeast cells [11]. Accordingly, under degenerative disease conditions (like in the case of neurodegenerative diseases) removal of oxidized proteins from brain may be beneficiary to halt the progression of the disease. One approach that has been used to achieve this goal was carried out by immunization of mice models of Alzheimer’s disease (AD) with a MetO-rich protein antigen. Apparently, this treatment reduced mouse brain plaque burden in the hippocampal region of the treated mice compared with non-treated mice [14]. It is speculated that the resulting anti-MetO antibodies [14], produced through this antigen immunization, interacted with MetO-proteins (including MetO-beta amyloid protein) and cleared them from brain (presumably through enhancing these proteins’ degradation). The overall importance of the Msr system to promote survival under physiological and enhanced oxidative stress conditions has been manifested in several organisms, from prokaryotes to eukaryotes including mammals. So far, methionine oxidation has been shown to affect many proteins’ activities [2]. In mammals, examples of proteins in which their MetO can be also reduced by the Msr system include: the potassium channel of the brain [26], an isoform of the inhibitory protein B [27-29], calmodulin [30,31], calcium/calmodulin-dependent protein kinase II [32], and D2-dopamine receptor [10]. Examples of such proteins in lower eukaryotes (not mammals) include: transcription regulator for head box O (FOXO) in fruit fly [33], and prion-like protein (Sup35) in yeast [34]. These findings suggest a key role for MsrA in regulating MetO reduction in proteins, including major survival regulator transcription factors like FOXO [33]. Genomic analysis of brain of MsrA knockout mouse revealed that lack of the MsrAgene in mouse causes a strong and significant up regulation of genes that are involved in redox homeostasis and transcription regulation [35]. These data strongly suggest that MetO formation and reduction by the Msr system play a major role in the cellular adaptation to oxidative stress conditions, which is mediated by expression regulation of specific transcription factors. However, up-to-date not much is known about the signaling events that are leading to the transcriptional regulation Editorial