RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration

Mar 8, 2007Human molecular genetics

RCAN1 (DSCR1) increases nerve cell vulnerability to oxidative stress, which may contribute to brain degeneration

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Abstract

RCAN1 gene dosage may influence neuronal resistance to oxidative stress-induced damage.

Rcan1(-/-) neurons show increased resistance to damage from hydrogen peroxide (H2O2).
RCAN1 overexpression or calcineurin inhibitors can revert the resistance observed in Rcan1(-/-) neurons.
Calcium loading after H2O2 exposure is similar in both Rcan1(+/+) and Rcan1(-/-) neurons.
Calcineurin and NFAT signaling pathways may protect against oxidative stress in both types of neurons.
The findings suggest that RCAN1 levels could play a role in susceptibility to neurodegenerative diseases.

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Oxidative stress (OS) underlies neuronal dysfunction in many neurodegenerative disorders. Regulator of Calcineurin 1 (RCAN1 or DSCR1) is a dose-sensitive gene whose overexpression has been linked to Down syndrome (DS) and Alzheimer's disease (AD) neuropathology and to the response of cells to stress stimuli. Here, we show that RCAN1 mRNA and protein expression are sensitive to OS in primary neurons, and we evaluate the involvement of RCAN1 dosage in neuronal death induced by OS. We find that Rcan1(-/-) neurons display an increased resistance to damage by H(2)O(2), which can be reverted by RCAN1 overexpression or by exogenous inhibitors of calcineurin. Although increased intracellular Ca(2+) concentration is an important factor in OS-mediated cell death, our results show that Ca(2+) loading after exposure to H(2)O(2) was similar in Rcan1(+/+) and Rcan1(-/-) neurons. Our data further suggest that CaN and NFAT signaling protect against OS in both Rcan1(+/+) and Rcan1(-/-) neurons. To explain the observed differential vulnerability, we therefore propose a mechanism downstream of H(2)O(2)-mediated Ca(2+) entry, involving calcineurin-NFAT signaling. These findings highlight the importance of RCAN1 gene dosage in the modulation of cell survival and death pathways and suggest that changes in the amount of RCAN1 could represent an important mechanism for regulating susceptibility to neurodegeneration, especially in DS and AD.

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RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration

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