Primary amoebic meningoencephalitis is a rare but fatal central nervous system (CNS) disease caused by the "brain-eating amoeba" Naegleria fowleri. A major obstacle is the requirement for drugs with the ability to cross the blood-brain barrier, which are used in extremely high doses, cause severe side effects, and are usually ineffective. We discovered that the 4-aminomethylphenoxy-benzoxaborole AN3057 exhibits nanomolar potency against N. fowleri, and experimental treatment of infected mice significantly prolonged survival and demonstrated a 28% relapse-free cure rate.

• MeSH
• amébiáza * farmakoterapie   MeSH
• hematoencefalická bariéra MeSH
• meningoencefalitida * MeSH
• myši MeSH
• Naegleria fowleri * MeSH
• protozoární infekce centrálního nervového systému * farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Frataxin is a small conserved mitochondrial protein; in humans, mutations affecting frataxin expression or function result in Friedreich's ataxia. Much of the current understanding of frataxin function comes from informative studies with yeast models, but considerable debates remain with regard to the primary functions of this ubiquitous protein. We exploit the tractable reverse genetics of Trypanosoma brucei in order to specifically consider the importance of frataxin in an early branching lineage. Using inducible RNAi, we show that frataxin is essential in T. brucei and that its loss results in reduced activity of the marker Fe-S cluster-containing enzyme aconitase in both the mitochondrion and cytosol. Activities of mitochondrial succinate dehydrogenase and fumarase also decreased, but the concentration of reactive oxygen species increased. Trypanosomes lacking frataxin also exhibited a low mitochondrial membrane potential and reduced oxygen consumption. Crucially, however, iron did not accumulate in frataxin-depleted mitochondria, and as T. brucei frataxin does not form large complexes, it suggests that it plays no role in iron storage. Interestingly, RNAi phenotypes were ameliorated by expression of frataxin homologues from hydrogenosomes of another divergent protist Trichomonas vaginalis. Collectively, the data suggest trypanosome frataxin functions primarily only in Fe-S cluster biogenesis and protection from reactive oxygen species.

• MeSH
• buněčné linie MeSH
• eukaryotické buňky fyziologie   klasifikace   MeSH
• exprese genu MeSH
• fenotyp MeSH
• financování organizované MeSH
• fylogeneze MeSH
• lidé MeSH
• mitochondriální proteiny genetika   chemie   metabolismus   MeSH
• molekulární evoluce MeSH
• molekulární sekvence - údaje MeSH
• prokaryotické buňky fyziologie   klasifikace   MeSH
• proteiny obsahující železo a síru genetika   chemie   metabolismus   MeSH
• proteiny vázající železo genetika   chemie   metabolismus   MeSH
• protozoální proteiny genetika   chemie   metabolismus   MeSH
• RNA interference MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• Trichomonas genetika   chemie   klasifikace   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH