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.

DOI: 10.1074/jbc.M110.177519

7 Figures and Tables

02004002011201220132014201520162017
Citations per Year

1,220 Citations

Semantic Scholar estimates that this publication has 1,220 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Sun2011RegulatorOC, title={Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase-3 activation.}, author={Xiulian Sun and Yili Wu and Bin Chen and Zhuohua Zhang and Weihui Zhou and Yigang Tong and Junying Yuan and Kun Xia and Hinrich Gronemeyer and Richard A Flavell and Weihong Song}, journal={The Journal of biological chemistry}, year={2011}, volume={286 11}, pages={9049-62} }