title: The calcineurin inhibitor Sarah (Nebula) exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease.
abstract: Expression of the Down syndrome critical region 1 (DSCR1) protein, an inhibitor of the Ca(2+)-dependent phosphatase calcineurin, is elevated in the brains of individuals 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 have also been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra; also known as 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 flies, whereas 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 RNA interference (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 upregulation or calcineurin downregulation in the brain might exacerbate Aβ42-associated neuropathogenesis in AD or DS.
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Soojin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Se Min
authors.initials: SM
authors.lastname: Bang
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Yoon Ki
authors.initials: YK
authors.lastname: Hong
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Jang Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Haemin
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Seung Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Oriental Medicine, Dongguk University, Gyeogju 38066, Republic of Korea Department of Oriental Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeonggi 10326, Republic of Korea.
authors.forename: Quan Feng
authors.initials: QF
authors.lastname: Liu
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Im-Soon
authors.initials: IS
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea kscho@konkuk.ac.kr.
authors.forename: Kyoung Sang
authors.initials: KS
authors.lastname: Cho
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D065095:Calcineurin Inhibitors / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D016923:Cell Death; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007814:Larva / Q000378:metabolism; D008136:Longevity; D008928:Mitochondria / Q000378:metabolism; D024521:Mushroom Bodies / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism*; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C513393:Sra protein, Drosophila; C075222:amyloid beta-protein (1-42); D009569:Nitric Oxide; D006861:Hydrogen Peroxide
keywords: Alzheimer's disease; Amyloid-β42; DSCR1 (RCAN1); Drosophila; sarah (nebula)