Annotated Bibliography

Benedini, S., Cortelli, P., Caumo, A., Terruzzi, I., Beelke, M., Perseghin, G., Montagna, P., Lugaresi, E., and Luzi, L. (2008). Insulin resistance to both glucose and aminoacid metabolism in a patient with Fatal Familial Insomnia. Nutrition, Metabolism and Cardiovascular Diseases 18, e47–e48. doi: 10.1016/j.numecd.2008.08.003

  • This study set out to investigate the lack of sleep model of FFI and its effect on intermediate metabolism, specifically glucose and amino acids. This was a case study because FFI patients are rare. The authors found that FFI induced insulin resistance. There is not a clear connection as to whether insulin resistance resulted from solely genetic mutations or from sleep deprivation.

Benito-León, J. (2004). Combined quinacrine and chlorpromazine therapy in fatal familial insomnia. Clin. Neuropharmacol. 27, 201–203. PMID: 15319710

  • The objective was to test the efficacy of quinacrine and chlorpromazine on two patients with FFI. They found the treatment to be ineffective. This was a failed attempt at a treatment to prion diseases.

Chakroun, N., Prigent, S., Dreiss, C.A., Noinville, S., Chapuis, C., Fraternali, F., and Rezaei, H. (2010). The oligomerization properties of prion protein are restricted to the H2H3 domain. The FASEB Journal 24, 3222–3231. doi: 10.1096/fj.09-153924

  • The findings of this study are significant in that they demonstrate that the physical characteristics of the oligomerized forms of the H2&H3 domains. What is equally important is that the authors show that the rest of the domains outside of the H2&H3 domains are NOT involved in oligomerization. Infectious oligomers form a ‘double beta hairpin.’ This information will be included in the molecular basis section.

Colombo, G., Meli, M., Morra, G., Gabizon, R., and Gasset, M. (2009). Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion. PLoS ONE 4, e4296. doi: 10.1371/journal.pone.0004296

  • This study aimed to investigate the misfolding of the cellular prion protein into the infectious neurodegenerative form. By oxidizing methionine, the authors conclude that the sulfoxidation of Helix-3 methionines may be the cause of the misfolding from the alpha helices into beta sheets. This implicates treatments/future work to prevent the onset of prion diseases.

Feng, B., Wang, Z., Liu, T., Jin, R., Wang, S., Wang, W., Xiao, G., and Zhou, Z. (2014). Methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant of the human prion protein. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1842, 2345–2356. doi: 10.1016/j.bbadis.2014.09.012

  • Here the authors go beyond that of Colombo & associates by affirming the previous researchers’ work and then characterizing the effects of oxidized methionines associated with the D178N mutant displaying FFI. They found that the oxidized methionines gave way to increased concentrations of beta sheet oligomers, enhanced resistance to proteinase K digestion, more frequent cell apoptosis, and higher numbers of aggregations and associated plaques. While these findings are significant at determining the pathway of infection and ultimately treatment, the groundwork is still being laid.

Froböse, T., Slawik, H., Schreiner, R., Veselý, Z., Wiegand, M., Bäuml, J., and Förstl, H. (2012). Agomelatine Improves Sleep in a Patient with Fatal Familial Insomnia. Pharmacopsychiatry 45, 34–36. doi: 10.1055/s-003101287778

  • This was a case study where a single patient with FFI was treated with agomelatine based on conjectures by Salva et al. While the patient did not recover from the illness, agomelatine did seem to be effective in alleviating some of the restlessness and insomnia experienced by the patient. This was obviously a small sample size and was more of a management then a cure, but it did show promise for future work. There was also concern that the results may have also been linked to consumption of sodium valproate (anticonvulsant).

Jackson, W.S., Borkowski, A.W., Watson, N.E., King, O.D., Faas, H., Jasanoff, A., and Lindquist, S. (2013). Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases. Proceedings of the National Academy of Sciences 110, 14759–14764. doi: 10.1073/pnas.1312006110

  • Since FFI is rare, occurs sporadically, and kills the affected individual in 12-18 months, testing on human patients and following the progression of the disease is difficult. This paper is significant because it effectively replicates the transmissibility and symptoms of the human prion diseases, FFI and CJD, in animals. Using knock-in mice, the study showed differences at a single amino acid being passed down to offspring, and the onset of the disease varying between individuals, but occurring sporadically. These mice induced with FFI may be valuable in determining therapies.

Korth, C., May, B.C.H., Cohen, F.E., and Prusiner, S.B. (2001). Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proceedings of the National Academy of Sciences 98, 9836–9841. doi: 10.1073/pnas.161274798

  • This work analyzed a variety of derivatives and suggested that quinacrine and chlorpromazine could act as antiprion reagents. Because these two compounds have had other successful uses in humans, they were deemed to be the most likely candidates for the difficult-to-treat prion diseases, including FFI. This work set the stage for that of Benito-León in 2004.
Lugaresi, E., Medori, R., Montagna, P., Baruzzi, A., Cortelli, P., Lugaresi, A., Tinuper, P., Zucconi, M., and Gambetti, P. (1986). Fatal Familial Insomnia and Dysautonomia with Selective Degeneration of Thalamic Nuclei. New England Journal of Medicine 315, 997–1003. doi: 10.1056/NEJM198610163151605
  • This article will be used for a historical introduction to point to the first documented case of FFI.

McDonald, A.J., Dibble, J.P., Evans, E.G.B., and Millhauser, G.L. (2014). A New Paradigm for Enzymatic Control of -Cleavage and -Cleavage of the Prion Protein. Journal of Biological Chemistry 289, 803–813. doi: 10.1074/jbc.M113.502351

  • The study is significant because, as stated in its name, it introduces a new mechanism. This work introduces different cleavage sites and suggests that alpha and beta cleavages may not be the result of differing mechanisms. ADAM proteins are proposed to possibly be the sole factor responsible in misguided cleavages. This study is full of valuable information for all sections and will be discussed in future work.

Medori, R., Tritschler, H.-J., LeBlanc, A., Villare, F., Manetto, V., Chen, H.Y., Xue, R., Leal, S., Montagna, P., Cortelli, P., et al. (1992). Fatal Familial Insomnia, a Prion Disease with a Mutation at Codon 178 of the Prion Protein Gene. New England Journal of Medicine 326, 444–449. doi: 10.1056/NEJM199202133260704

  • This was some of the earlier work on FFI by the authors who first named and characterized the disease state. This study is valuable for providing groundwork and historical context of the disease. Tissue from control, FFI, and CJD individuals were assessed with antibodies to PrP and the presence or absence of proteinase K. The authors conclude that codon 178 of the PrP gene is the point mutation inducing FFI.

Pamplona, R., Naudí, A., Gavín, R., Pastrana, M.A., Sajnani, G., Ilieva, E.V., del Río, J.A., Portero-Otín, M., Ferrer, I., and Requena, J.R. (2008). Increased oxidation, glycoxidation, and lipoxidation of brain proteins in prion disease. Free Radical Biology and Medicine 45, 1159–1166. doi: 10.1016/j.freeradbiomed.2008.07.009

  • This study is valuable to implicate the metabolic pathway of the prion disease. The infectious prion protein of FFI was found to increase the activity of the metal-catalyzed oxidation, lipoxidation, and glycoxidation pathways. This finding contributes to an increased knowledge of the patheogenesis of human prion disease.

Pan, K.M., Baldwin, M., Nguyen, J., Gasset, M., Serban, A., Groth, D., Mehlhorn, I., Huang, Z., Fletterick, R.J., and Cohen, F.E. (1993). Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc. Natl. Acad. Sci. U.S.A. 90, 10962–10966. PMID: 7902575

  • This is an earlier article but gives the fundamentals on the differences between normal and infectious prion proteins. They emphasize the differences in alpha helix and beta sheet percentages between PrPsc and PrPc which is the result of a post translational chemical modification from PrPc. PrPsc tend to aggregate due to higher beta sheet composition.

Petersen, R.B., Parchi, P., Richardson, S.L., Urig, C.B., and Gambetti, P. (1996). Effect of the D178N Mutation and the Codon 129 Polymorphism on the Metabolism of the Prion Protein. Journal of Biological Chemistry 271, 12661–12668. doi: 10.1074/jbc.271.21.12661

  • This article was meant for background information; note it is from 1996. These authors established the now commonly held D178N mutation and the codon 129 polymorphism associated with the formation of misfolded protein oligomers and is at the heart of CJD, Gerstmann-Straussler-Scheinker syndrome, and most importantly, FFI. Interestingly, infectious PrP was partially corrected with glycosylation.

Requena, J.R., Dimitrova, M.N., Legname, G., Teijeira, S., Prusiner, S.B., and Levine, R.L. (2004). Oxidation of methionine residues in the prion protein by hydrogen peroxide. Archives of Biochemistry and Biophysics 432, 188–195. doi: 10.1016/

  • This study observes the oxidation of methionine sites of prion proteins in vitro with hydrogen peroxide. The authors come to suggest that this oxidation has a destabilizing effect and contributes to the formation of infectious prion proteins. The discussion has rich structural data as to the quaternary interactions between prion proteins and the effects of oxidation.

Rossetti, G., Cong, X., Caliandro, R., Legname, G., and Carloni, P. (2011). Common Structural Traits across Pathogenic Mutants of the Human Prion Protein and Their Implications for Familial Prion Diseases. Journal of Molecular Biology 411, 700–712. doi: 10.1016/j.jmb.2011.06.008

  • This work delves into how structure relates to function and has some very nice figures. They find that enough mutations in the human prion protein gene alters the alpha structure to beta and disrupts the stability of the protein, converting it to the infectious type. These authors are suggestive of future work.

Salva, M.-A.Q., Vanier, B., Laredo, J., Hartley, S., Chapotot, F., Moulin, C., Lofaso, F., and Guilleminault, C. (2007). Major depressive disorder, sleep EEG and agomelatine: an open-label study. The International Journal of Neuropsychopharmacology 10, 691-696. doi: 10.1017/S1461145707007754

  • Agomelatine is a new antidepressant that has been found to normalize sleep wake cycle. This drug acts as a melatonin agonist and serotonin antagonist. This study confirmed those of other human subjects and animal subjects. Agomelatine was hypothesized to be effective in other psychotic diseases that interfere with sleep. This work set the stage for Froböse et al.

Shi, Q., Chen, L.-N., Zhang, B.-Y., Xiao, K., Zhou, W., Chen, C., Zhang, X.-M., Tian, C., Gao, C., Wang, J., et al. (2015). Proteomics analyses for the global proteins in the brain tissues of different human prion diseases. Mol. Cell Proteomics. doi: 10.1074/mcp.M114.038018

  • This was a proteomics study that looked at the brain tissues of individuals with various prion diseases and compared them to that of a ‘normal’ control. A large number of proteins were identified to be misfolded, up- and downregulated in patients with prion diseases. The authors go on to conclude that their findings suggest affection to the lysosome, oxidative phosphorylation, protein export, and drug metabolism pathways. This paper is interesting because associations were discussed between prion and other neurodegenerative diseases.

Shi, Q., Xie, W.-L., Zhang, B., Chen, L.-N., Xu, Y., Wang, K., Ren, K., Zhang, X.-M., Chen, C., Zhang, J., and Dong, X.-P. (2013). Brain microglia were activated in sporadic CJD but almost unchanged in fatal familial insomnia and G114V genetic CJD. Virology Journal 10, 216-224. doi: 10.1186/1743-422X-10-216

  • This study has implications in future treatments. The aim was to determine the activity of microglia in individuals with FFI, G114V, and sCJD, which they did. How microglia interact in these prion diseases gives insight into the pathogenesis of FFI, and by extention, avenues for further research and treatment.

Spiegel, K., Leproult, R., and Van Cauter, E. (1999). Impact of sleep debt on metabolic and endocrine function. The Lancet 354, 1435–1439. doi: 10.1016/S0140-6736(99)01376-8

  • This study has implications in FFI by exhibiting the metabolic reprecussions of sleep deprivation. By limiting total bed time from 12 to 4 hours per night, the results showed that glucose tolerance and thyrotropin concentrations were lower and that cotrisol concentrations and sympathetic nervous system activity were increased in those with ‘sleep debt.’ Since insomnia is a major component of FFI, deleterious effects such as these may account for the rapid mental and physical degradation between onset and death of inflicted individuals.

Tasali, E., Leproult, R., Ehrmann, D.A., and Van Cauter, E. (2008). Slow-wave sleep and the risk of type 2 diabetes in humans. Proceedings of the National Academy of Sciences 105, 1044–1049. doi: 10.1073/pnas.0706446105

  • This study is significant because it describes the consequences associated with sleep deprivation as experienced in FFI. The paper shows that specific reduction of slow-wave sleep resulted in decreased insulin sensitivty without a greater increase in insulin release. Decreased insulin sensitivity results in a decreased breakdown of blood glucose and puts individuals at an increased chance for developing type 2 diabetes.

Watt, N.T. (2005). Reactive Oxygen Species-mediated -Cleavage of the Prion Protein in the Cellular Response to Oxidative Stress. Journal of Biological Chemistry 280, 35914–35921. doi:10.1074/jbc.M507327200

  • This article address the metabolic signficance of PrPC in regard to copper cation regulation and resistance to oxidative stress. The study determines that protection against oxidative stress is the result of a beta cleavage of PrPc early in the pathway. This study provides valuable physical and metabolic information about prion proteins.

Wolschner, C., Giese, A., Kretzschmar, H.A., Huber, R., Moroder, L., and Budisa, N. (2009). Design of anti- and pro-aggregation variants to assess the effects of methionine oxidation in human prion protein. Proceedings of the National Academy of Sciences 106, 7756–7761. doi: 10.1073/pnas.0902688106

  • This study provides mechanistic evidence of the oxidation of methionine. The conversion of alpha helices to beta sheets via a hydrophilic and more chemically similar analogue was shown. The hydrophobic analogue retained its alpha helices structures. This study affirmed the somewhat assumed speculations regarding methionine oxidation and its relation to plaque and beta sheet formations.

Xu, Z., Prigent, S., Deslys, J.-P., and Rezaei, H. (2011). Dual Conformation of H2H3 Domain of Prion Protein in Mammalian Cells. Journal of Biological Chemistry 286, 40060–40068. doi: 10.1074/jbc.M111.275255

  • This paper was meant more for background. The important information is that the H2&H3 domains are parts of the prion protein where misfolding are attributed to and from which infectious oligomers originate. This paper gives some biochemical properties of the domain such as an amyloid conformation and resistance to proteinase K.

Yin, S., Yu, S., Li, C., Wong, P., Chang, B., Xiao, F., Kang, S.-C., Yan, H., Xiao, G., Grassi, J., et al. (2006). Prion Proteins with Insertion Mutations Have Altered N-terminal Conformation and Increased Ligand Binding Activity and Are More Susceptible to Oxidative Attack. Journal of Biological Chemistry 281, 10698–10705. doi: 10.1074/jbc.M511819200

  • Prion proteins can also have insertion mutations of octapeptide repeats. The N-terminal on repeat mutants are more exposed for both antibody binding and oxidative damages. The more insertions (3 vs. 5), the more severe the symptoms associated with a give prion disease. This article could go in future work with the suggestion of using these over-exposed N-terminal for disease management.

Yu, S., Zhang, Y., Li, S., Sy, M.-S., Sun, S., Tien, P., and Xiao, G. (2007). Early onset fatal familial insomnia with rapid progression in a Chinese family line. Journal of Neurology 254, 1300–1301. doi:10.1007/s00415-006-0517-0

  • This is a fascinating case study of one of the few individuals who experienced the onset of FFI in his early twenties. A pedigree of the family is detailed in this case study, and certain facts may be abstracted for historical and metabolic contexts. Case studies are important because they provide real accounts that an audience can connect with.