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The Journal of Neuroscience, June 25, 2008, 28(26):6539-6548; doi:10.1523/JNEUROSCI.5685-07.2008

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Cellular/Molecular
Aging Impairs the Unfolded Protein Response to Sleep Deprivation and Leads to Proapoptotic Signaling

Nirinjini Naidoo,^1,2 Megan Ferber,² Monali Master,² Yan Zhu,² and Allan I. Pack^1,2

¹Division of Sleep Medicine and ²Center for Sleep and Respiratory Neurobiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Nirinjini Naidoo, Center for Sleep, University of Pennsylvania School of Medicine, Translational Research Laboratories Room 2116, 125 South 31st Street, Philadelphia, PA 19104. Email: naidoo{at}mail.med.upenn.edu

Protein misfolding, accumulation, and aggregation characterize many aging-related diseases. Protein aggregates do not accumulate in unstressed cells primarily because of the existence of competent cellular "quality control" machinery. The endoplasmic reticulum (ER) is a major part of this quality control system. Accumulation of misfolded proteins in the ER causes ER stress and activates a signaling pathway called the unfolded protein response (UPR). The UPR limits protein load by upregulating ER chaperones such as Ig binding protein (BiP)/glucose-regulated protein 78 (GRP78) and by attenuating protein translation through eukaryotic initiation factor 2 (eIF2) phosphorylation. Acute sleep deprivation (6 h) in young mice leads to induction of the UPR with upregulation of BiP/GRP78 and attenuation of protein translation. We demonstrate here that aging impairs this adaptive response to sleep deprivation. Aged mice do not display an increase in BiP expression with acute sleep deprivation. In addition, there is decreased basal expression of BiP/GRP78 in aged mice. There is a decline in eIF2 phosphorylation in aged mouse cerebral cortex that is associated with higher levels of GADD34 (growth arrest and DNA damage 34) and proapoptotic proteins such as CCAAT/enhancer-binding protein-homologous protein and activated caspase-12, suggesting that young animals possess an efficient ER adaptive response that declines with aging.

Key words: sleep deprivation; aging; ER stress; UPR; apoptotic signaling; BiP

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Received Dec. 21, 2007; revised May 5, 2008; accepted May 6, 2008.

Correspondence should be addressed to Nirinjini Naidoo, Center for Sleep, University of Pennsylvania School of Medicine, Translational Research Laboratories Room 2116, 125 South 31st Street, Philadelphia, PA 19104. Email: naidoo{at}mail.med.upenn.edu

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