Expression of the Down syndrome critical region 1 (DSCR1) protein, an inhibitor of the Ca2+-dependent phosphatase calcineurin, is elevated in the brains of patients with Down syndrome (DS) or Alzheimer's disease (AD). Although increased levels of DSCR1 were often observed to be deleterious to neuronal health, its beneficial effects against AD neuropathology also have been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra)/nebula, a Drosophila DSCR1 ortholog, in amyloid-β42 (Aβ42)-induced neurological phenotypes in Drosophila. We detected sra expression in the mushroom bodies of the fly brain, which are a center for learning and memory in flies. Moreover, similar to humans with AD, Aβ42-expressing flies showed increased Sra levels in the brain, demonstrating that the expression pattern of DSCR1 with regard to AD pathogenesis is conserved in Drosophila. Interestingly, overexpression of sra using the UAS-GAL4 system exacerbated the rough eye phenotype, decreased survival rates, and increased neuronal cell death in Aβ42-expressing flies without modulating Aβ42 expression. Moreover, neuronal overexpression of sra in combination with Aβ42 dramatically reduced both locomotor activity and the adult lifespan of Aβ42-expressing flies, while flies with overexpression of sra alone showed normal climbing ability albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of calcineurin such as FK506 and cyclosporin A, or knockdown of calcineurin expression by RNAi, exacerbated the Aβ42-induced rough eye phenotype. Furthermore, sra-overexpressing flies displayed significantly decreased mitochondrial DNA and ATP levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that sra overexpression augments Aβ42 cytotoxicity in Drosophila suggest that DSCR1 up-regulation or calcineurin down-regulation in the brain may exacerbate Aβ42-associated neuropathogenesis in AD or DS.
- Received September 1, 2014.
- Accepted November 28, 2015.
- © 2015. Published by The Company of Biologists Ltd
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