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Friedreich ataxia is a human neurodegenerative and myocardial
disease caused by decreased expression of the mitochondrial protein
frataxin. Proteomic analysis of the mutant yeast model of Friedreich
ataxia presented in this paper reveals that these cells display
increased amounts of proteins involved in antioxidant defenses,
including manganese-superoxide dismutase. This enzyme shows,
however, lower activity than that found in wild type cells. Our
results indicate that this lack of activity is a consequence of cellular
manganese deficiency, because in manganese-supplemented cultures,
cell manganese content, and manganese-superoxide dismutase
activity were restored. One of the hallmarks of Friedreich
ataxia is the decreased activity of iron/sulfur-containing enzymes.
The activities of four enzymes of this group (aconitase, glutamate
synthase, succinate dehydrogenase, and isopropylmalate dehydratase)
have been analyzed for the effects of manganese supplementation.
Enzyme activities were recovered by manganese treatment,
except for aconitase, for which, a specific interaction with
frataxin has been demonstrated previously. Similar results were
obtained when cells were grown in iron-limited media suggesting
that manganese-superoxide dismutase deficiency is a consequence
of iron overload. In conclusion, these data indicate that generalized
deficiency of iron-sulfur protein activity could be a consequence of
manganese-superoxide dismutase deficiency, and consequently, it
opens new strategies for Friedreich ataxia treatment.
This work was supported in part by Friedreich Ataxia Research Alliance (Arlington, VA) and Grants BFU2004-00593/BMC and GEN2001-4707C08-06 from the Ministerio de Educación y Ciencia (Spain). |
