Regulator of Calcineurin 1 (RCAN1) Facilitates Neuronal Apoptosis through Caspase-3 Activation

Jan 11, 2011The Journal of biological chemistry

Regulator of calcineurin 1 (RCAN1) may promote nerve cell death by activating caspase-3

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Abstract

RCAN1 expression is elevated in the cortex of individuals with Down syndrome and Alzheimer disease.

Individuals with Down syndrome may develop Alzheimer disease neuropathology after middle age.
Alzheimer disease neuropathology is characterized by neuritic plaques, neurofibrillary tangles, and neuronal loss.
Elevated RCAN1 expression could be linked to neurodegeneration in both Down syndrome and Alzheimer disease.
Dexamethasone, a stress hormone, may activate RCAN1 expression.
Overexpression of RCAN1-1 in neurons activates caspase-9 and caspase-3, leading to neuronal apoptosis.
Neurotoxicity associated with RCAN1-1 may be reduced by knocking out caspase-3 in specific neurons.

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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.

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Regulator of Calcineurin 1 (RCAN1) Facilitates Neuronal Apoptosis through Caspase-3 Activation

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