Many aging related diseases such as Alzheimer's, and Parkinson's are characterized by protein misfolding, accumulation and aggregation. The fact that protein aggregates do not accumulate in unstressed cells is due in part to the existence of cellular """"""""quality control"""""""" machinery. One such quality control system is the endoplasmic reticulum (ER). It suppresses the formation of aggregates by ensuring fidelity of transcription and translation, by chaperoning nascent or unfolded proteins, and by selectively degrading improperly folded polypeptides before they can aggregate. The ER has evolved highly specific signaling pathways to ensure that its protein folding capacity is not overwhelmed. These pathways collectively called the unfolded protein response (UPR) are required if the cell is to survive the ER stress. If this equilibrium is disturbed the ER stress response is induced; there is an up regulation of chaperones with attenuation of protein synthesis. This process is seen as cytoprotective. We see evidence of this during sleep deprivation: with as little as 6 hours of sleep deprivation we see an induction of the ER stress response pathway. While it is not clear what in sleep deprivation would induce an ER stress-like response, it is known that certain stimuli such as reduced glucose/energy, perturbations in Ca 2+ levels, and reactive oxygen species (ROS) induce ER stress. It is also known that protein accumulation in the ER, and disturbances in calcium homeostasis lead to an increase in ROS and activation of NF?B. What is evident is that several factors can induce the UPR, resulting in decreased global protein expression, and if the stress is severe, oxidative damage and possibly aggregation of proteins if the stress is not suitably relieved. Whether these changes in protein occur during sleep deprivation is currently unknown and will be assessed in this project. It is not known what the effect of age is on the ER stress response and the UPR. ER chaperones are increasingly oxidized in mouse liver with age suggesting that there may be an impaired ER stress response, as defective chaperone molecules will impact on the chaperoning system. Further, there is likely to be increased vulnerability to cellular stress as these chaperones are key participants in an anti-stress mechanism. Thus, there are likely to be alterations in the aging brain to this aspect of the response to sleep deprivation. The overall hypothesis of this proposal is that sleep deprivation leads to alterations in proteins in the endoplasmic reticulum and that the magnitude of this change is age-dependent. To address this global hypothesis, we have the following specific aims: 1) We propose that sleep deprivation results in decreased protein expression in the ER and oxidative change to a subset of proteins and 2) We hypothesize that this effect of sleep deprivation is altered in older animals with in particular more evidence of oxidative change. We will use 2-D DIGE, as well as oxidation assays and mass spectrometry, to identify proteins that are altered by aging and sleep deprivation in the ER.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG025353-02
Application #
6951449
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (O1))
Program Officer
Monjan, Andrew A
Project Start
2004-09-30
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$190,200
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Naidoo, Nirinjini (2009) Cellular stress/the unfolded protein response: relevance to sleep and sleep disorders. Sleep Med Rev 13:195-204
Naidoo, Nirinjini; Ferber, Megan; Master, Monali et al. (2008) Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J Neurosci 28:6539-48
Pawlyk, Aaron C; Ferber, Megan; Shah, Aanal et al. (2007) Proteomic analysis of the effects and interactions of sleep deprivation and aging in mouse cerebral cortex. J Neurochem 103:2301-13