The Msr System and Age Related Diseases

It is now established that in age-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and cataractogenesis, oxidized proteins accumulate [85-87]. Furthermore, methionine oxidation has been observed in neurodegenerative diseases despite high expression of the MsrA protein in the cerebellum and neurons of rat brain [67]. Indeed, Gabbita et al. [88] revealed a decrease in MsrA activity in all brain regions studied in an Alzheimer patient compared with control subjects. This decrease in MsrA activity was accompanied by an increase in brain protein carbonyl levels. In Parkinson's disease, it was shown that a-synuclein oxidation plays a critical role in the disease. a-synuclein contains four methionines that are all solvent-exposed. It was shown that oxidation of these methion-ine residues inhibited its fibrillation and could thus be an important factor in Parkinson's disease if Msr activity is impaired during this pathology [89]. However, it was shown that sulfur-containing amino acids are sensitive to oxidation during cataractogenesis and that methionine sulfoxide in proteins accumulates in the cataract lens [90-92], although a high MsrA content was still found in the lens [93] and no decrease in MsrA activity was detected in cataracteous lenses [94]. All these studies highlight the importance of methionine oxidation in the development of degenerative diseases. Indeed, the Msr system may have a role in these degenerative pathologies, as inferred by MsrA-/- knock-out mice that develop psychological disorders (tip-toe walking) [69]. Taken together, these results suggest that loss of MsrA activity in the brain may provoke severe neurological dysfunctions.

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