History & Metabolic Context

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.

Figure 1. Unspecified hypnogram to illustrate REM and the various stages of NREM sleep. (Source: google images)
Figure 1. Unspecified hypnogram to illustrate REM and the various stages of NREM sleep. (Source: google images)

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.

Figure 2. Results of cytokine levels in patients with different TSEs. Measured by ELISA kits. Shows mean +/- ST.DEV. (Source: Shi et. al. 2013)
Figure 2. Results of cytokine levels in patients with different TSEs. Measured by ELISA kits. Shows mean +/- ST.DEV. (Source: Shi et. al. 2013)

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.

To Continue:

The Genetic and Biomolecular Basis for FFI

FFI Disease Treatment and Maintenance

What’s Up Next with FFI

Return to:

General Overview

For the full list of references please see:

Annotated Bibliography

4 Replies to “History & Metabolic Context”

  1. Hi Ryan! I read all of your pages, but figured I would just leave one comment referencing several pages instead of commenting on each individual page. Overall I found your project to be very interesting and comprehensive! Great job! I have a few questions!

    1. Does FFI prevent patients from getting any sleep at all? It seems like the big issue here is the lack of SWS. So are patients getting some rest, but just not getting any SWS or are they literally incapable of sleeping? If they are incapable of sleeping at all, how can researchers be sure that the issue is actually due to lack of SWS instead of lack of sleep in general?

    2. You mentioned on this page that patients experience decreased insulin function, yet I didn’t see an associated symptom of diabetes anywhere. Are FFI patients supplemented with insulin to correct for this? How are they compensating in a way as to not acquire some form of diabetes?

    3. How do you test or screen for FFI? It seems like families with a history of FFI are offered genetic testing, although that is not entirely conclusive. Do patients just present with insomnia and then undergo genetic testing at that time? Are there any screens other than genetic testing?

    4. I am interested in the late onset of the disease. Is it that people have the mutation their entire life and just haven’t built up enough scrapie to cause any symptoms until later in life? I wonder if perhaps epigenetics are at play here. It seems possible that this gene could be mutated from birth but then turned on by some other factor later in life. Could sleep deprivation be having some kind of impact that turns on epigenetic modification causing prions and then subsequent prion accumulation?

    5. In terns of the D173N mutation causing FFI, is it the loss of D or the addition of N that is causing the problem? Has anyone done experiments to mutate the D to other residues and see if it results in similar symptoms? If you mutate a neighboring residue to N, do you still get a problem, indicating that the presence of the N in that general area of the protein is what is problematic?

    6. I was wondering if you could clarify the sentence on your molecular basis page that reads, “Misfolding events are induced solely by the endogenous protein and are independent of external agents.” I am unclear as to the two options you are setting up here and the point you are trying to make. Perhaps you could give an example from each side?

    7. Do you have any ideas for why we don’t see the typical presentation of prion disease here with spongiform like degredation and proteinase K resistance?

    8. I was also wondering what kind of animal models were being used for many of these experiments. In a paper we read earlier in the semester we emphasized the importance of not using nocturnal animals (which many lab rodents are) as test subjects for experiments dealing with sleep issues. Does this play a role here?

    9. On the treatment page you mentioned agomelatine being used in a case study and successfully managing FFI. Id this a wide spread therapy or just a clinical trial/early lab test?

    10. In terms of treatment, are the majority of proposed therapies targeted at managing symptoms or actually prolonging lifespan with FFI?

    11. Has anyone attempted to make a modified statin drug that could be used as a treatment? Perhaps one that has the same therapeutic effects for FFI, but doesn’t have such a high cholesterol inhibition? Is the same part of the statin active in managing cholesterol and attempted management of FFI?

    Thanks so much! 🙂

    1. Hi Kelly, these are all very great questions. I will do the best I can to answer them all…

      1. Most individuals completely lose the ability to sleep. The loss of SWS is significant because that seems to have the greatest physical impacts, but for the most part they don’t get any types of sleep. The researchers aren’t entirely sure, they only hypothesize that the most detriment is from loss of SWS.
      2. Patients do experience decreased insulin sensitivity and thus have a greater chance of developing type 2 diabetes.
      3. I’m not sure that there is a noninvasive procedure to go into someone’s brain and test their levels of cellular and scrapie prion proteins. Our best bet is a genetic test that shows a D178N mutation. But, like you said, even that is not entirely conclusive as the disease displays incomplete penetrance.
      4. I have not seen anything between sleep deprivation and prion accumulation. The first half of what you said was correct. There appears to be a critical concentration of scrapie prion protein required to display neurotoxic effects even though it is accumulating since birth. Accumulations may increase as a function of age and an increased presence of ROS in cells.
      5. I honestly don’t know about how the substitution causes the disease to onset. Me and matt were discussing that the 129M mutation may increase the affinity of the protein as a whole for oxidation.
      6. That is also a very good question. I was saying that the folding of the protein is it’s own doing. There does not appear to be a chaperone protein that assists with folding like there are for many other proteins.
      7. Again, I don’t have a great answer for you. This was no more than an observation…
      8. I don’t think the use of rodents to replicate FFI is a tremendous problem because whether or not you sleep at day or night, the body maintains a circadian rhythm, which would still be disrupted.
      9. The agolmelatine treatment that I found was a case study so its validation is still contingent on many more treatments, but in the mean time it seemed to be helpful!
      10. The quinacrine/chlorpromazine therapy was supposed to be really effective because it got at the heart of the disease, scrapie prions. This type of treatment is ideal. The successful agomelatine treatment was targeted at the symptoms, however. Both are important, although I’d say addressing the infectious proteins is more so.
      11. The problem with statins wasn’t that they were inhibiting cholesterol too much, but rather that the amount of cholesterol required to have a bioactive effect was too high. In this sense, we just can’t survive with how little cholesterol would be required to mediate the disease state. The problem isn’t the drugs, it’s us being needy hahaha.

      I tried my best to answer all the questions as accurately and concisely as possible. I hope this helped your understanding of the disease. I appreciate you taking the time to really understand how this all works and for engaging me with questions. You rock, thanks again!

  2. Hi Ryan, I guess I didn’t realize this…but not all prion diseases are “infectious”? What qualifies a prion disease as infectious? I thought you can to consume affected tissue…which perhaps is not occurring in the case of FFI?

    1. Good question Dr. Colabroy. I have misused that word in this case. The authors of that article define prion disease as spontaneous, inherited and infectious… I was thinking it was infectious because it does spread through the brain, but they were specifically referring to the ability of the disease to be transmitted from one organism to another… Like eating cattle meat with infectious prions that then spread into humans. I have removed that sentence.

Comments are closed.