title: Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase-3 activation.
abstract: Individuals with Down syndrome (DS) will inevitably develop Alzheimer disease (AD) neuropathology sometime after middle age, which may be attributable to genes triplicated in individuals with DS. The characteristics of AD neuropathology include neuritic plaques, neurofibrillary tangles, and neuronal loss in various brain regions. The mechanism underlying neurodegeneration in AD and DS remains elusive. Regulator of calcineurin 1 (RCAN1) has been implicated in the pathogenesis of DS. Our data show that RCAN1 expression is elevated in the cortex of DS and AD patients. RCAN1 expression can be activated by the stress hormone dexamethasone. A functional glucocorticoid response element was identified in the RCAN1 isoform 1 (RCAN1-1) promoter region, which is able to mediate the up-regulation of RCAN1 expression. Here we show that overexpression of RCAN1-1 in primary neurons activates caspase-9 and caspase-3 and subsequently induces neuronal apoptosis. Furthermore, we found that the neurotoxicity of RCAN1-1 is inhibited by knock-out of caspase-3 in caspase-3(-/-) neurons. Our study provides a novel mechanism by which RCAN1 functions as a mediator of stress- and Aβ-induced neuronal death, and overexpression of RCAN1 due to an extra copy of the RCAN1 gene on chromosome 21 contributes to AD pathogenesis in DS.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Xiulian
authors.initials: X
authors.lastname: Sun
authors.forename: Yili
authors.initials: Y
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.forename: Yigang
authors.initials: Y
authors.lastname: Tong
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C108612:RCAN1 protein, human; C548050:RCAN1 protein, rat; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3