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.
Highlights
The highly conserved prion protein (PrP) is encoded by the PRNP gene [1] and exists predominately in two conformationally different isoforms [2]
The incubation period between inoculation and disease onset is prolonged in prion diseases [11], providing a potential window for neuroprotective interventions [14], but this relies on knowledge of the molecular mechanisms responsible for neuronal loss so that intervention can be targeted effectively and
Identifying such mechanisms is complicated by the fact that different prion disease types target pathology to rather different areas of the brain and the information that causes neuropathological targeting is believed to be encoded in the structure of PrPSc
Summary
The highly conserved prion protein (PrP) is encoded by the PRNP gene The incubation period between inoculation and disease onset is prolonged in prion diseases [11], providing a potential window for neuroprotective interventions [14], but this relies on knowledge of the molecular mechanisms responsible for neuronal loss so that intervention can be targeted effectively and Identifying such mechanisms is complicated by the fact that different prion disease types (or strains) target pathology to rather different areas of the brain and the information that causes neuropathological targeting is believed to be encoded in the structure of PrPSc. multimeric forms of PrPSc may be toxic to neurons directly, by activating signaling pathways that lead to apoptosis or necrosis, it is possible that the neuropathology that arises with PrPSc propagation occurs in combination with loss of function of PrPC [15]. We review whether there may be role for PrPC loss of function in the sleep-wake cycle, a key biological system that is compromised to different extents during various prion diseases
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