Human Molecular Genetics Advance Access originally published online on March 6, 2007
Human Molecular Genetics 2007 16(9):1039-1050; doi:10.1093/hmg/ddm049
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RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration
1 Genes and Disease Program, 2 Bioinformatics and Genomics Program, Center for Genomic Regulation (CRG-UPF), Biomedical Research Park Building, E-08003 Barcelona, Catalonia, Spain and 3 Molecular Physiology and Channelopathies, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain
* To whom correspondence should be addressed at: Genes and Disease Program, Genomic Regulation Center (CRG-UPF), Biomedical Research Park, C/Dr Aiguader 88, E-08003 Barcelona, Catalonia, Spain. Tel: +34 933160201; Fax: +34 933160099; Email: eulalia.marti{at}crg.es
Received November 27, 2006; Revised February 19, 2007; Accepted February 28, 2007
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 H2O2 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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