PHILADELPHIA –Researchers at the School of Medicine have shown that the unfolded protein response, which is an adaptive response to stress induced by sleep deprivation, is impaired in the brains of old mice.
The findings suggest that inadequate sleep in the elderly, who normally experience sleep disturbances, could exacerbate an already-impaired protective response to protein misfolding that happens in aging cells. “Protein misfolding and aggregation is associated with many diseases like Alzheimer’s and Parkinson’s,” notes first author Nirinjini Naidoo, PhD, Assistant Professor in the Division of Sleep Medicine. The study appears in the June issue of the Journal of Neuroscience.
The unfolded protein response (UPR) is one part of the quality control system for monitoring protein synthesis in the endoplasmic reticulum, the cellular compartment where some proteins are made. In this study, researchers found that the UPR was activated in 10-week old, sleep-deprived mice, so that misfolded proteins did not accumulate in the endoplasmic reticulum of brain cells in the cerebral cortex. However, in two-year-old, sleep-deprived mice, the UPR failed to do its job and misfolded proteins clogged the endoplasmic reticulum. Old mice that were not stressed by sleep deprivation were shown to already have an impaired UPR.
Sleep in mice is characterized by short periods of inactivity throughout the day and night. On average, mice sleep approximately one hour for every two they are awake. In order to deprive mice of sleep, researchers constantly monitored and gently stroked the mice with a brush to disturb periods of inactivity.
At 3, 6, 9, or 12 hours of sleep deprivation, proteins were examined from the mouse brains. By six hours of sleep deprivation, young mice demonstrated that the UPR system was in place because protein synthesis was shut off by a chaperone protein called BiP/GRP78. In contrast, there was no BiP/GRP78 in old mice so protein synthesis continued.
Old mice also had less of the proteins that refold abnormal proteins than young mice, and old mice had more of the proteins that cause cell death than young mice. Thus, several processes are upset in old mouse brains by sleep deprivation, and the overall result is a further accumulation of misfolded proteins.
“We could speculate that sleep disturbance in older humans places an additional burden on an already-stressed protein folding and degradation system,” says Naidoo.
Future studies will examine whether augmenting key protective proteins delays the effects of aging and reduces sleep disturbances.
Study co-authors are Megan Ferber, Monali Master, Yan Zhu and Allan Pack, all of Penn. The study was funded by the National Institute on Aging.
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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $425 million awarded in the 2018 fiscal year.
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