ABSTRACT
The tau mutation in the Syrian hamster resides in the enzyme casein kinase 1 epsilon (CK1epsilon), resulting in a dramatic acceleration of wheel-running activity cycles to about 20 hours. tau also impacts growth, energy, metabolism, feeding behavior, and circadian mechanisms underpinning seasonal timing, causing accelerated reproductive and neuroendocrine responses to photoperiodic changes. Modeling and experimental studies suggest that tau acts as a gain of function on specific residues of PER, consistent with hamster studies showing accelerated degradation of PER in the suprachiasmatic nucleus in the early circadian night. We have created null and tau mutants of Ck1epsilon in mice. Circadian period lengthens in CK1epsilon(/), whereas CK1epsilon(tau/tau) shortens circadian period of behavior in vivo in a manner nearly identical to that of the Syrian hamster. CK1epsilon(tau/tau) also accelerates molecular oscillations in peripheral tissues, demonstrating its global circadian role. CK1epsilon(tau) acts by promoting degradation of both nuclear and cytoplasmic PERIOD, but not CRYPTOCHROME, proteins. Our studies reveal that tau acts as a gain-of-function mutation, to accelerate degradation of PERIOD proteins. tau has consistent effects in both hamsters and mice on the circadian organization of behavior and metabolism, highlighting the global impact of this mutation on mammalian clockwork in brain and periphery.
Subject(s)
Casein Kinase 1 epsilon/genetics , Casein Kinase 1 epsilon/physiology , Circadian Rhythm/genetics , Circadian Rhythm/physiology , Activity Cycles , Animals , CLOCK Proteins , Casein Kinase 1 epsilon/deficiency , Cricetinae , Cryptochromes , Female , Flavoproteins/genetics , Flavoproteins/physiology , Male , Mesocricetus , Mice , Mice, Knockout , Mice, Mutant Strains , Models, Biological , Mutation , Neurosecretory Systems/physiology , Photoperiod , Seasons , Species Specificity , Trans-Activators/genetics , Trans-Activators/physiologyABSTRACT
Stressful stimuli activate the heat shock (stress) response in which a set of heat shock proteins (hsps) is induced, which play roles in cellular repair and protective mechanisms. Most studies in the mammalian nervous system have focused on Hsp70, however, the present investigation targets other members of the induced set, namely Hsp27 and Hsp32. In response to hyperthermia, these hsps are strongly induced in Bergmann glial cells in the rat brain and transported into their radial fibers, which project into the 'synaptic-enriched' molecular layer of the cerebellum. Using subcellular fractionation and immunoelectron microscopy, hyperthermia-induced Hsp27 and Hsp32 were detected in synaptic elements and in perisynaptic glial processes. These results suggest that stress-induced Hsp27 and Hsp32 may contribute to repair and protective mechanisms at the synapse.
Subject(s)
Cerebellum/metabolism , Fever/metabolism , Heat-Shock Proteins/metabolism , Neoplasm Proteins/metabolism , Oxygenases , Synapses/metabolism , Animals , Cerebellum/chemistry , HSP27 Heat-Shock Proteins , Heat-Shock Response , Heme Oxygenase (Decyclizing) , Immunohistochemistry , Male , Rats , Rats, Wistar , Subcellular Fractions , Synapses/chemistryABSTRACT
Heat-shock proteins are induced in response to cellular stress. Although heat-shock proteins are known to function in repair and protective mechanisms, their relationship to critical neural processes, such as synaptic function, has received little attention. Here we investigate whether the major heat-shock protein Hsp70 localizes to the synapse following a physiologically relevant increase in temperature in the mammalian nervous system. Our results indicate that hyperthermia-induced Hsp70 is associated with pre- and postsynaptic elements, including the postsynaptic density. The positioning of Hsp70 at the synapse could facilitate the repair of stress-induced damage to synaptic proteins and also contribute to neuroprotective events at the synapse.
