RT Journal Article
SR Electronic
T1 Aging Impairs the Unfolded Protein Response to Sleep Deprivation and Leads to Proapoptotic Signaling
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6539
OP 6548
DO 10.1523/JNEUROSCI.5685-07.2008
VO 28
IS 26
A1 Nirinjini Naidoo
A1 Megan Ferber
A1 Monali Master
A1 Yan Zhu
A1 Allan I. Pack
YR 2008
UL http://www.jneurosci.org/content/28/26/6539.abstract
AB 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 α (eIF2α) 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 eIF2α 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.