Human prion diseases are also known as human transmissible spongiform encephalopathies (TSEs). TSEs are neurodegenerative diseases that can take sporadic, genetic or acquired (infectious) forms. (Korth et. al. 2001)The TSE of interest is Fatal Familial Insomnia (FFI), but some other commonly known infectious TSEs are Kuru, Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease. (Shi et. al. 2015) FFI is genetically inherited and has a mean onset of 51 years of age, although the disease state has occurred in an individual as young as 15 and in seven individuals between 21-25. (Yu et. al. 2006) Individuals die, on average, 18 months after initiation of the disease state. FFI was first documented by Lugaresi & colleagues in Italy, 1986. They hypothesized that loss of neurons in the thalamus, specifically degradation of the anterior and dorsomedial thalamic regions, was significant due to its various roles in sleep-wake cycles and autonomic functions.
The most obvious feature of FFI is untreatable insomnia, which contributes to many of the other disease conditions. Metabolic and hormonal variability has been observed in individuals with sleep debt in as short a time as seven days. (Spiegel et. al. 1999) More so, mammalian sleep cycles are composed of periods of rapid-eye-movement (REM) and non-REM (NREM) sleep, which is further broken into stages 1-4. Stages 3 and 4 of NREM are named Slow-Wave Sleep (SWS). SWS is the deepest and most restorative for systems such as memory consolidation. (Tasali et. al. 2007) The entrance into SWS decreases brain glucose production and use, inhibits corticotropic activity and decreases sympathetic nervous activity. In accordance with these statements, Tasali & associates (2007) found that loss of SWS induced decreased insulin sensitivity (IS) without a compensatory increase in insulin production.
FFI results in neurological dysfunctions such as hypertension, tachycardia, pyrexia, hyperhidrosis, irregular breathing, dysarthria, ataxic gait and myoclonus. (Benedini et. al. 2008) Likewise, circadian endocrine regulation is impaired for growth hormone, prolactin, follicle-stimulating hormone and cortisol. In a case study, Benedini & others (2008) found that an individual with FFI developed insulin resistance to glucose and protein metabolism without a predisposition to such. Hypertension found in individuals with FFI could possibly be connected to sleep debt. (Spiegel et. al. 1999) Some believe that the most of the distressing symptoms of FFI are the result of chronic sleep deprivation and they could dramatically dissipate by acquiring sleep. (Frobose et. al. 2012)
Interestingly, chronic loss of NREM sleep, lowered IS and increased risk of diabetes are also typical characteristics of aging. (Tasali et. al. 2007) The disease state of FFI can be thought of as ‘hyper-aging,’ if you will, in that the characteristics of FFI and aging overlap, and individuals die quickly after onset.
Microglial cells are mononuclear phagocytes in the CNS that function to mount an immune response. Against a disease, microglial cells can respond to release cyto/chemokines, nitric oxide, free radicals and neurotropic molecules. (Shi et. al. 2013) More so, microglial cells have specific and various responses to the different human prion diseases. As seen in Figure 2, IL-1-beta, IL-6 and TNF-alpha release are, for the most part, stunted below that found in the control. From this information, the authors were able to conclude that recruitment of inflammatory cells for neuronal destruction of the thalamus is not occurring in FFI and is not responsible for the disease state.
As of 2006, 27 familial pedigrees of individuals with FFI have been constructed and all of them contained a D178N point mutation in the prion protein gene (PRNP). The term ‘prion’ is derived from the phrase ‘protein infection’ that describes the ability of the protein to replicate and propagate. (Xu et. al. 2011) The mutated cellular prion protein (PrPC) can undergo a tertiary conformational change to an infectious ‘scrapie’ form (PrPSc). PrPC converts its alpha-helices to beta-sheets as a PrPSc, which has implications in its inter- and intra-protein interactions.
The conformational change and propagation of PrPSc has been well documented since the early 1990’s. (Pan et. al. 1993) The interactions between PrPSc and the central nervous system (CNS) impairs function, induces structural damage and causes disease in the CNS. (Yu et. al. 2006) Shi et. al. (2013) believes that the lack of detectable plaques and low levels of PrPSc, compared to other prion diseases, may be responsible for the lack of cyto/chemokines produced by microglial cells, as seen in Figure 2.
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