title: Sleep deprivation induces the unfolded protein response in mouse cerebral cortex.
abstract: Little is known about the molecular mechanisms underlying sleep. We show the induction of key regulatory proteins in a cellular protective pathway, the unfolded protein response (UPR), following 6 h of induced wakefulness. Using C57/B6 male mice maintained on a 12:12 light/dark cycle, we examined, in cerebral cortex, the effect of different durations of prolonged wakefulness (0, 3, 6, 9 and 12 h) from the beginning of the lights-on inactivity period, on the protein expression of BiP/GRP78, a chaperone and classical UPR marker. BiP/GRP78 expression is increased with increasing durations of sleep deprivation (6, 9 and 12 h). There is no change in BiP/GRP78 levels in handling control experiments carried out during the lights-off period. PERK, the transmembrane kinase responsible for attenuating protein synthesis, which is negatively regulated by binding to BiP/GRP78, is activated by dissociation from BiP/GRP78 and by autophosphorylation. There is phosphorylation of the elongation initiation factor 2alpha and alteration in ribosomal function. These changes are first observed after 6 h of induced wakefulness. Thus, prolonging wakefulness beyond a certain duration induces the UPR indicating a physiological limit to wakefulness.
authors.affiliation: Division of Sleep Medicine/Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. naidoo@mail.med.upenn.edu
authors.forename: Nirinjini
authors.initials: N
authors.lastname: Naidoo
authors.forename: William
authors.initials: W
authors.lastname: Giang
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Galante
authors.forename: Allan I
authors.initials: AI
authors.lastname: Pack
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002540:Cerebral Cortex / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D011489:Protein Denaturation / Q000502:physiology*; D012892:Sleep Deprivation / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D014157:Transcription Factors; D019892:eIF-2 Kinase; C000717248:Hspa5 protein, mouse