The Role of the Mammalian Prion Protein in the Control of Sleep

Abstract

Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases where it can be the defining dysfunction, as in the case of the “eponymous” fatal familial insomnia, or an early-stage symptom as in certain types of Creutzfeldt-Jakob disease. It is important to establish the role of the cellular prion protein (PrPC), the key molecule involved in prion pathogenesis, within the sleep-wake system in order to understand fully the mechanisms underlying its contribution to both healthy circadian rhythmicity and sleep dysfunction during disease. Although severe disruption to the circadian rhythm and melatonin release is evident during the pathogenic phases of some prion diseases, untangling whether PrPC plays a role in circadian rhythmicity, as suggested in mice deficient for PrPC expression, is challenging given the lack of basic experimental research. We provide a short review of the small amount of direct literature focused on the role of PrPC in melatonin and circadian rhythm regulation, as well as suggesting mechanisms by which PrPC might exert influence upon noradrenergic and dopaminergic signaling and melatonin synthesis. Future research in this area should focus upon isolating the points of dysfunction within the retino-pineal pathway and further investigate PrPC mediation of pinealocyte GPCR activity.

Circulating miRNAs are associated with sleep duration in children/adolescents: Results of the I.Family Study

“…In our analysis, the top predicted target of differential miRNAs was PrP C , a cell surface protein mainly known for its notorious role in prion diseases (Wulf, Senatore, & Aguzzi, ). Of note, recent evidence suggests a role of PrPC in sleep regulation through noradrenergic and dopaminergic signalling and melatonin synthesis, possibly modulating both healthy circadian activity rhythms and patterns, and sleep dysfunction during neurodegenerative disorders (Roguski & Gill, ).…”

Melanopsin Retinal Ganglion Cells and Pupil: Clinical Implications for Neuro-Ophthalmology

“…In conclusion, the use of PLR mediated by mRGCs, as a measure of mRGC function, is of particular relevance for neurodegenerative disorders for which there is already evidence of circadian and sleep dysfunction, such as PD, AD, and HD. Similarly, it might be also relevant for other neurological disorders with evidence of circadian dysfunction such as frontotemporal dementia (71), Lewy-Body dementia (72), Progressive Supranuclear Palsy (73, 74), and possibly prion diseases, in particular fatal familial insomnia (75). Moreover, the study of PLR mediated by mRGCs might be particularly intriguing for conditions, in which light sensitivity is a predominant feature, such as photophobia (76, 77) and photosensitivity in epilepsy (78).…”

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

“…There has been a longstanding interest in the role of PRPC in sleep particularly as mutations in PRPC cause the prion disease fatal insomnia. PRPC regulates sleep and circadian rhythmicity (Roguski and Gill, 2017) and mouse studies indicate roles in governing sleep cycles and regulating sleep after periods of sleep deprivation (Dossena et al, 2008;Tobler et al, 1997).…”