The @entity53921 inhibitor, Sarah/Nebula, exacerbates Ab42 phenotypes in a XXXX model of @entity195 .

@entity1 @entity72410 @entity137 @entity55686 @entity53921 @entity205 @entity195 @entity141 @entity1140 @entity238 @entity855
UNASSIGNED: Expression of the Down syndrome critical region 1 ( @entity55686 ) protein, an inhibitor of the @entity141 -dependent phosphatase @entity53921 , is elevated in the brains of @entity1 with Down syndrome (DS) or @entity195 ( @entity195 ). Although increased levels of @entity55686 were often observed to be deleterious to neuronal health, its beneficial effects against @entity195 neuropathology also have been reported, and the roles of @entity55686 on the pathogenesis of @entity195 remain controversial. Here, we investigated the role of sarah ( @entity72410 )/nebula, a @entity238 @entity55686 ortholog, in amyloid-b42 (Ab42)-induced neurological phenotypes in @entity238 . We detected @entity72410 expression in the mushroom bodies of the @entity238 brain, which are a center for learning and memory in flies. Moreover, similar to @entity1 with @entity195 , Ab42-expressing flies showed increased @entity72410 levels in the brain, demonstrating that the expression pattern of @entity55686 with regard to @entity195 pathogenesis is conserved in @entity238 . Interestingly, overexpression of @entity72410 using the UAS-GAL4 system exacerbated the rough eye phenotype, decreased survival rates, and increased neuronal cell death in Ab42-expressing flies without modulating Ab42 expression. Moreover, neuronal overexpression of @entity72410 in combination with Ab42 dramatically reduced both locomotor activity and the adult lifespan of Ab42-expressing flies, while flies with overexpression of @entity72410 alone showed normal climbing ability albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of @entity53921 such as @entity1140 and @entity205 , or knockdown of @entity53921 expression by RNAi, exacerbated the Ab42-induced rough eye phenotype. Furthermore, @entity72410 -overexpressing flies displayed significantly decreased mitochondrial DNA and @entity855 levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that @entity72410 overexpression augments Ab42 @entity137 in @entity238 suggest that @entity55686 up-regulation or @entity53921 down-regulation in the brain may exacerbate Ab42-associated neuropathogenesis in @entity195 or DS.
