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

Sílvia Porta, Selma A. Serra, Meritxell Huch, Miguel A. Valverde, Franc Llorens, Xavier P. Estivill, Maria L. Arbonés, Eulàlia Martí

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

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 H2O2, which can be reverted by RCAN1 overexpression or by exogenous inhibitors of calcineurin. Although increased intracellular Ca2+ concentration is an important factor in OS-mediated cell death, our results show that Ca2+ loading after exposure to H2 O2 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 H2O2-mediated Ca2+ 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.

Original languageEnglish
Pages (from-to)1039-1050
Number of pages12
JournalHuman Molecular Genetics
Volume16
Issue number9
DOIs
Publication statusPublished - May 2007
Externally publishedYes

Fingerprint

Oxidative Stress
Neurons
Calcineurin
Down Syndrome
Alzheimer Disease
Cell Death
Gene Dosage
Neurodegenerative Diseases
Cell Survival
Messenger RNA
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress : A potential pathogenic process in neurodegeneration. / Porta, Sílvia; Serra, Selma A.; Huch, Meritxell; Valverde, Miguel A.; Llorens, Franc; Estivill, Xavier P.; Arbonés, Maria L.; Martí, Eulàlia.

In: Human Molecular Genetics, Vol. 16, No. 9, 05.2007, p. 1039-1050.

Research output: Contribution to journalArticle

Porta, Sílvia ; Serra, Selma A. ; Huch, Meritxell ; Valverde, Miguel A. ; Llorens, Franc ; Estivill, Xavier P. ; Arbonés, Maria L. ; Martí, Eulàlia. / RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress : A potential pathogenic process in neurodegeneration. In: Human Molecular Genetics. 2007 ; Vol. 16, No. 9. pp. 1039-1050.
@article{a14275cc4b5d4254a8d66ccaa6001436,
title = "RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: A potential pathogenic process in neurodegeneration",
abstract = "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 H2O2, which can be reverted by RCAN1 overexpression or by exogenous inhibitors of calcineurin. Although increased intracellular Ca2+ concentration is an important factor in OS-mediated cell death, our results show that Ca2+ loading after exposure to H2 O2 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 H2O2-mediated Ca2+ 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.",
author = "S{\'i}lvia Porta and Serra, {Selma A.} and Meritxell Huch and Valverde, {Miguel A.} and Franc Llorens and Estivill, {Xavier P.} and Arbon{\'e}s, {Maria L.} and Eul{\`a}lia Mart{\'i}",
year = "2007",
month = "5",
doi = "10.1093/hmg/ddm049",
language = "English",
volume = "16",
pages = "1039--1050",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "9",

}

TY - JOUR

T1 - RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress

T2 - A potential pathogenic process in neurodegeneration

AU - Porta, Sílvia

AU - Serra, Selma A.

AU - Huch, Meritxell

AU - Valverde, Miguel A.

AU - Llorens, Franc

AU - Estivill, Xavier P.

AU - Arbonés, Maria L.

AU - Martí, Eulàlia

PY - 2007/5

Y1 - 2007/5

N2 - 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 H2O2, which can be reverted by RCAN1 overexpression or by exogenous inhibitors of calcineurin. Although increased intracellular Ca2+ concentration is an important factor in OS-mediated cell death, our results show that Ca2+ loading after exposure to H2 O2 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 H2O2-mediated Ca2+ 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.

AB - 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 H2O2, which can be reverted by RCAN1 overexpression or by exogenous inhibitors of calcineurin. Although increased intracellular Ca2+ concentration is an important factor in OS-mediated cell death, our results show that Ca2+ loading after exposure to H2 O2 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 H2O2-mediated Ca2+ 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.

UR - http://www.scopus.com/inward/record.url?scp=34447306022&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447306022&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddm049

DO - 10.1093/hmg/ddm049

M3 - Article

C2 - 17341486

AN - SCOPUS:34447306022

VL - 16

SP - 1039

EP - 1050

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 9

ER -