Circadian regulation of prion protein messenger RNA in the rat forebrain: a widespread and synchronous rhythm

doi:10.1016/S0306-4522(99)00092-5

Neuroscience

Volume 91, Issue 4, July 1999, Pages 1201-1204

https://doi.org/10.1016/S0306-4522(99)00092-5 Get rights and content

Abstract

Although the expression of the normal prion protein in the host is critical to the development of transmissible spongiform encephalopathies,¹⁶ the physiological role of this protein and the processes regulating its expression remain obscure. We now report that the messenger RNA for the prion protein is regulated in the rat brain in a marked circadian manner not only in the suprachiasmatic nuclei, the principal site for the generation of mammalian circadian rhythms,¹⁴ but also in other forebrain regions. The data show a remarkable consistency in the concurrence of a single peak of prion protein messenger RNA at each of the sites early in the animal's phase of increased locomotor activity; behavioural arousal does not, however, appear to affect this expression. We believe this to be the first study demonstrating that the expression of prion protein messenger RNA can change over a relatively short period in vivo.

The results are discussed with reference to the range of recently discovered “clock-related” transcripts which also have widespread tissue expression; these include the messenger RNAs for D-box binding protein and thyroid embryonic factor, transcription factors which bind to the prion protein promoter.¹²

Section snippets

Conclusions

The present study has detected a remarkably synchronous circadian rhythm in PrP^c mRNA at various sites in the rat forebrain; an identical pattern of expression was observed during the LD cycle and during DD. We believe this to be the first study demonstrating that the expression of PrP^c mRNA can change over a relatively short period in vivo. Understanding the processes that underlie this dynamic regulation may elucidate the control of circadian rhythms that are expressed concurrently at

Acknowledgments

This work was supported by the Biotechnology and Biological Sciences Research Council, U.K.

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Cited by (25)

Circadian clocks and neurodegenerative diseases: Time to aggregate?
2013, Current Opinion in Neurobiology
Citation Excerpt :
Disturbed sleep is a feature of prion diseases [63], not least fatal familial insomnia [64], and the absence of prion protein in mice alters sleeping patterns [65]. As for reciprocal effects, however, little is known, although circadian expression of mRNA encoding prion protein has been reported in rat brain [66]. In the absence of knowledge as to how prion-like aggregates may transmit pathology, it is difficult to divine circadian modulation of the underlying mechanisms [1], other than to highlight the strong circadian modulation of the expression of synaptic vesicle-cycling proteins in brain that would influence opportunities for exocytosis and endocytosis that could underlie prion-like intercellular transmission [25•].
The major neurodegenerative diseases are characterised by a disabling loss of the daily pattern of sleep and wakefulness, which may be reflective of a compromise to the underlying circadian clock that times the sleep cycle. At a molecular level, the canonical property of neurodegenerative diseases is aberrant aggregation of otherwise soluble neuronal proteins. They can thus be viewed as disturbances of proteostasis, raising the question whether the two features — altered daily rhythms and molecular aggregation — are related. Recent discoveries have highlighted the fundamental contribution of circadian clocks to the correct ordering of daily cellular metabolic cycles, imposing on peripheral organs such as the liver a strict programme that alternates between anabolic and catabolic states. The discovery that circadian mechanisms are active in local brain regions suggests that they may impinge upon physiological and pathological elements that influence pro-neurodegenerative aggregation. This review explores how introducing the dimension of circadian time and the circadian clock might refine the analysis of aberrant aggregation, thus expanding our perspective on the cell biology common to neurodegenerative diseases.
Identification of adjacent binding sites for the YY1 and E4BP4 transcription factors in the ovine PrP (Prion) gene promoter
2009, Journal of Biological Chemistry
Citation Excerpt :
This is of interest in light of the observation that PrPc itself may exhibit a role in circadian rhythms as shown for prn-p knock-out mice (33) and suggested by the symptoms of fatal familial insomnia (FFI), a prion disease in humans in which patients initially suffer from interrupted sleep patterns (34). In fact, prn-p mRNA has been shown to be regulated in a circadian manner (35). The observation that E4BP4, which has defined roles in the regulation of circadian rhythms, interacts specifically with the PrP gene promoter may prove important for the understanding of the normal function of PrPc and the mechanisms of TSE pathogenesis and susceptibility.
The PrP gene encodes the cellular isoform of the prion protein (PrP^c) which has been shown to be crucial to the development of transmissible spongiform encephalopathies (TSEs). PrP knock-out mice, which do not express endogenous PrP^c, exhibit resistance to TSE disease. The regulation of PrP gene expression represents, therefore, a crucial factor in the development of TSEs. Two sequence motifs in the PrP promoter (positions –287 to –263 from transcriptional start) were previously reported as being highly conserved, and it was suggested that they represent binding sites for as yet unidentified transcription factors. To test this hypothesis, binding of nuclear proteins was analyzed by electrophoretic mobility shift assays using ovine or murine cells and tissues with radiolabeled DNA probes containing the conserved motif sequences. Specific binding was observed to both motifs, and polymorphic variants of these motifs exhibited differential binding. Two proteins bound to these motifs were identified as the Yin Yang 1 (YY1) (motif 1) and E4BP4 (motif 2) transcription factors. Functional promoter analysis of four different promoter variants revealed that motif 1 (YY1) was associated with inhibitory activity in the context of the PrP promoter, whereas motif 2 (E4BP4) was linked to a slight enhancing activity. This represents the first demonstration of binding of nuclear factors to two highly conserved DNA sequence motifs within mammalian PrP promoters. The action of these factors on the PrP promoter is haplotype-specific, leading us to propose that the prion protein expression pattern and, with it, the distribution of TSE infectivity may be associated with PrP promoter genotype.
The prion protein family: Diversity, rivalry, and dysfunction
2007, Biochimica et Biophysica Acta - Molecular Basis of Disease
The prion gene family currently consists of three members: Prnp which encodes PrP^C, the precursor to prion disease associated isoforms such as PrP^Sc; Prnd which encodes Doppel, a testis-specific protein involved in the male reproductive system; and Sprn which encodes the newest PrP-like protein, Shadoo, which is expressed in the CNS. Although the identification of numerous candidate binding partners for PrP^C has hinted at possible cellular roles, molecular interpretations of PrP^C activity remain obscure and no widely-accepted view as to PrP^C function has emerged. Nonetheless, studies into the functional interrelationships of prion proteins have revealed an interesting phenomenon: Doppel is neurotoxic to cerebellar cells in a manner which can be blocked by either PrP^C or Shadoo. Further examination of this paradigm may help to shed light on two prominent unanswered questions in prion biology: the functional role of PrP^C and the neurotoxic pathways initiated by PrP^Sc in prion disease.
Prion protein accumulation and neuroprotection in hypoxic brain damage
2004, American Journal of Pathology
The function of the normal conformational isoform of prion protein, PrP^C, remains unclear although lines of research have suggested a role in the cellular response to oxidative stress. Here we investigate the expression of PrP^C in hypoxic brain tissues to examine whether PrP^C is in part regulated by neuronal stress. Cases of adult cerebral ischemia and perinatal hypoxic-ischemic injury in humans were compared with control tissues. PrP^C immunoreactivity accumulates within neuronal processes in the penumbra of hypoxic damage in adult brain, and within neuronal soma in cases of perinatal hypoxic-ischemic injury, and in situ hybridization analysis suggests an up-regulation of PrP mRNA during hypoxia. Rodents also showed an accumulation of PrP^C in neuronal soma within the penumbra of ischemic lesions. Furthermore, the infarct size in PrP-null mice was significantly greater than in the wild type, supporting the proposed role for PrP^C in the neuroprotective adaptive cellular response to hypoxic injury.
Elevated silver, barium and strontium in antlers, vegetation and soils sourced from CWD cluster areas: Do Ag/Ba/Sr piezoelectric crystals represent the transmissible pathogenic agent in TSEs?
2004, Medical Hypotheses
High levels of Silver (Ag), Barium (Ba) and Strontium (Sr) and low levels of copper (Cu) have been measured in the antlers, soils and pastures of the deer that are thriving in the chronic wasting disease (CWD) cluster zones in North America in relation to the areas where CWD and other transmissible spongiform encephalopathies (TSEs) have not been reported. The elevations of Ag, Ba and Sr were thought to originate from both natural geochemical and artificial pollutant sources – stemming from the common practise of aerial spraying with `cloud seeding' Ag or Ba crystal nuclei for rain making in these drought prone areas of North America, the atmospheric spraying with Ba based aerosols for enhancing/refracting radar and radio signal communications as well as the spreading of waste Ba drilling mud from the local oil/gas well industry across pastureland. These metals have subsequently bioconcentrated up the foodchain and into the mammals who are dependent upon the local Cu deficient ecosystems. A dual eco-prerequisite theory is proposed on the aetiology of TSEs which is based upon an Ag, Ba, Sr or Mn replacement binding at the vacant Cu/Zn domains on the cellular prion protein (PrP)/sulphated proteoglycan molecules which impairs the capacities of the brain to protect itself against incoming shockbursts of sound and light energy. Ag/Ba/Sr chelation of free sulphur within the biosystem inhibits the viable synthesis of the sulphur dependent proteoglycans, which results in the overall collapse of the Cu mediated conduction of electric signals along the PrP-proteoglycan signalling pathways; ultimately disrupting GABA type inhibitory currents at the synapses/end plates of the auditory/circadian regulated circuitry, as well as disrupting proteoglycan co-regulation of the growth factor signalling systems which maintain the structural integrity of the nervous system. The resulting Ag, Ba, Sr or Mn based compounds seed piezoelectric crystals which incorporate PrP and ferritin into their structure. These ferrimagnetically ordered crystals multireplicate and choke up the PrP-proteoglycan conduits of electrical conduction throughout the CNS. The second stage of pathogenesis comes into play when the pressure energy from incoming shock bursts of low frequency acoustic waves from low fly jets, explosions, earthquakes, etc. (a key eco-characteristic of TSE cluster environments) are absorbed by the rogue `piezoelectric' crystals, which duly convert the mechanical pressure energy into an electrical energy which accumulates in the crystal-PrP-ferritin aggregates (the fibrils) until a point of `saturation polarization' is reached. Magnetic fields are generated on the crystal surface, which initiate chain reactions of deleterious free radical mediated spongiform neurodegeneration in surrounding tissues. Since Ag, Ba, Sr or Mn based piezoelectric crystals are heat resistant and carry a magnetic field inducing pathogenic capacity, it is proposed that these ferroelectric crystal pollutants represent the transmissible, pathogenic agents that initiate TSE.
Does an infrasonic acoustic shock wave resonance of the manganese 3+ loaded/copper depleted prion protein initiate the pathogenesis of TSE?
2003, Medical Hypotheses
Intensive exposures to natural and artificial sources of infrasonic acoustic shock (tectonic disturbances, supersonic aeroplanes, etc.) have been observed in ecosystems supporting mammalian populations that are blighted by clusters of traditional and new variant strains of transmissible spongiform encephalopathy (TSE). But TSEs will only emerge in those ‘infrasound-rich’ environments which are simultaneously influenced by eco-factors that induce a high manganese (Mn)/low copper (Cu)–zinc (Zn) ratio in brains of local mammalian populations. Since cellular prion protein (PrPc) is a cupro-protein expressed throughout the circadian mediated pathways of the body, it is proposed that PrP’s Cu component performs a role in the conduction and distribution of endogenous electromagnetic energy; energy that has been transduced from incoming ultraviolet, acoustic, geomagnetic radiations. TSE pathogenesis is initiated once Mn substitutes at the vacant Cu domain on PrPc and forms a nonpathogenic, protease resistant, ‘sleeping’ prion. A second stage of pathogenesis comes into play once a low frequency wave of infrasonic shock metamorphoses the piezoelectric atomic structure of the Mn 3+ component of the prion, thereby ‘priming’ the sleeping prion into its fully fledged, pathogenic TSE isoform – where the paramagnetic status of the Mn 3+ atom is transformed into a stable ferrimagnetic lattice work, due to the strong electron–phonon coupling resulting from the dynamic ‘Jahn-Teller’ type distortions of the oxygen octahedra specific to the trivalent Mn species. The so called ‘infectivity’ of the prion is a misnomer and should be correctly defined as the contagious field inducing capacity of the ferrimagnetic Mn 3+ component of the prion; which remains pathogenic at all temperatures below the ‘curie point’. A progressive domino-like ‘metal to ligand to metal’ ferrimagnetic corruption of the conduits of electromagnetic superexchange is initiated. The TSE diseased brain can be likened to a solar charged battery on continuous charge; where the Mn contaminated/Cu depleted circadian-auditory pathways absorb and pile up, rather than conduct the vital life force energies of incoming ultra violet, acoustic and geomagnetic radiation. Instead of harnessing these energies for the body’s own bio-rhythmic requirements, an infrasonic shock induced metamorphosis of the Mn atom intervenes; initiating an explosive pathogenesis that perverts the healthy pathways of darkness and light; Cu prions are replaced by hyperpolarized Mn 3+ prions that seed self perpetuating ‘cluster bombs’ of free radical mediated neurodegeneration. TSE ensues.

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Neuroscience

Abstract

Section snippets

Conclusions

Acknowledgments

References (25)

A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light

Cell

A serum shock induces circadian gene expression in mammalian tissue culture cells

Cell

Nearly ubiquitous tissue distribution of the scrapie agent precursor protein

Neurology

The mRNA encoding the scrapie agent protein is present in a variety of non-neuronal cells

Acta neuropath., Berlin

Circadian changes of type II adenylyl cyclase mRNA in the rat suprachiasmatic nuclei

Brain Res.

Circadian changes in PACAP type 1 (PAC₁) receptor mRNA in the rat suprachiasmatic and supraoptic nuclei

Brain Res.

Circadian variation of EAAC1 glutamate transporter messenger RNA in the rat suprachiasmatic nuclei

Molec. Brain Res.

Circadian changes of glutamate decarboxylase 65 and 67 mRNA in the rat suprachiasmatic nuclei

NeuroReport

Variation in the expression of the mRNA for protein kinase C isoforms in the rat suprachiasmatic nuclei, caudate putamen and cerebral cortex

Molec. Brain Res.

Circadian changes in the expression of vasoactive intestinal peptide 2 receptor mRNA in the rat suprachiasmatic nuclei

Molec. Brain Res.

Sleep, genes and death: fatal familial insomnia

Brain Res. Rev.

The two PAR leucine zipper proteins, TEF and DBP, display similar circadian and tissue-specific expression, but have different target promoter preferences

Eur. molec. Biol. Org. J.

Cited by (25)

Circadian clocks and neurodegenerative diseases: Time to aggregate?

Identification of adjacent binding sites for the YY1 and E4BP4 transcription factors in the ovine PrP (Prion) gene promoter

The prion protein family: Diversity, rivalry, and dysfunction

Prion protein accumulation and neuroprotection in hypoxic brain damage

Elevated silver, barium and strontium in antlers, vegetation and soils sourced from CWD cluster areas: Do Ag/Ba/Sr piezoelectric crystals represent the transmissible pathogenic agent in TSEs?

Does an infrasonic acoustic shock wave resonance of the manganese 3+ loaded/copper depleted prion protein initiate the pathogenesis of TSE?

Letter to NeuroscienceCircadian regulation of prion protein messenger RNA in the rat forebrain: a widespread and synchronous rhythm

Abstract

Section snippets

Conclusions

Acknowledgments

A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light

Cell

A serum shock induces circadian gene expression in mammalian tissue culture cells

Cell

Nearly ubiquitous tissue distribution of the scrapie agent precursor protein

Neurology

The mRNA encoding the scrapie agent protein is present in a variety of non-neuronal cells

Acta neuropath., Berlin

Circadian changes of type II adenylyl cyclase mRNA in the rat suprachiasmatic nuclei

Brain Res.

Circadian changes in PACAP type 1 (PAC1) receptor mRNA in the rat suprachiasmatic and supraoptic nuclei

Brain Res.

Circadian variation of EAAC1 glutamate transporter messenger RNA in the rat suprachiasmatic nuclei

Molec. Brain Res.

Circadian changes of glutamate decarboxylase 65 and 67 mRNA in the rat suprachiasmatic nuclei

NeuroReport

Variation in the expression of the mRNA for protein kinase C isoforms in the rat suprachiasmatic nuclei, caudate putamen and cerebral cortex

Molec. Brain Res.

Circadian changes in the expression of vasoactive intestinal peptide 2 receptor mRNA in the rat suprachiasmatic nuclei

Molec. Brain Res.

Sleep, genes and death: fatal familial insomnia

Brain Res. Rev.

The two PAR leucine zipper proteins, TEF and DBP, display similar circadian and tissue-specific expression, but have different target promoter preferences

Eur. molec. Biol. Org. J.

Letter to Neuroscience
Circadian regulation of prion protein messenger RNA in the rat forebrain: a widespread and synchronous rhythm

Circadian changes in PACAP type 1 (PAC₁) receptor mRNA in the rat suprachiasmatic and supraoptic nuclei