Annotated Bibliography

➔      Prusiner, S. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).

DOI: 10.1126/science.6801762

◆     Old though it may be, this paper is essentially where everything began for CJD. I have chosen to talk about, but generally omit all literature prior to the proposal of prions as an infectious agent. CJD is inseparably entangled in a web of other transmissible spongiform encephalopathies, and so despite being about scrapie, and not CJD, Prusiner’s first proposal of prions is a landmark article and is cited in nearly every later article dealing with any prion disease.


➔      Fatal Flaws: How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain. Jay Ingram. Yale University Press, New Haven, CT, 2013.

ISBN: 9780300189896.

◆     This book is essentially a review of the entire quest for the infectious agent of numerous transmissible spongiform encephalopathies, like CJD. Although it will likely not be useful in a more technical analysis of CJD, it is an invaluable resource for a semi-scientifically literate audience first being introduced to prions and specifically, CJD.


➔      Lloyd, S. E., Mead, S. & Collinge, J. Genetics of prion diseases. Current Opinion in Genetics & Development 23, 345–351 (2011).

DOI: 10.1016/j.gde.2013.02.012

◆     This article reviews much of the work done since 2010 in CJD. It highlights genomic and proteomic work, and the discovery of two additional genetic loci other than PrP which may be important to CJD progression. It also discusses links to other neurodegenerative diseases and characterizes CJD as fairly unique among them

➔      Palmer, M., Dryden, A., Hughes, T. & Collinge, J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease. Nature 340–342 (1991).

DOI: 10.1038/352340a0

◆     In this paper, researchers identify a single amino acid polymorphism in PRNP which appears to predispose individuals to developing CJD. They link this isoform of the protein with the disease in individuals with CJD. The authors perform genetic studies to determine frequencies of various genotypes with respect to these two alleles in the general population and in those who developed sporadic CJD.


➔      Beck, J. A. et al. PRNP allelic series from 19 years of prion protein gene sequencing at the MRC Prion Unit. Human Mutation 31, E1551–E1563 (2010).

DOI: 10.1002/humu.21281

◆     Comprehensive review of pathogenic mutations and polymorphisms in PRNP. Specific focus on CJD, background information on PRNP. This review takes a more molecular focus than many of the other papers which are clinical reviews or case studies. They indicate that among all the studies they synthesize together, there seems not to be a strong single or even small number of mutation sites which lead to CJD, and rather any kind of destabilizing mutation plays out its disease phenotype in PrP:PrP interactions.


➔      Kaski, D. N. et al. Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors. Brain 134, 1829–1838 (2011).

DOI: 10.1093/brain/awr079

◆     This paper begins to tease out the highly complex genetic background of CJD as it relates to PRNP. It sets apart CJD from other neurodegenerative disorders by comparative work. The authors also do haplotype analyses which are a great point to work off of. They implicate a specific haplotype in susceptibility to prion diseases and suggest that part of the problem may be a mutation causing overexpression of PRNP.


➔      Collinge, J. et al. Prion dementia without characteristic pathology. The Lancet 336, 7–9 (1990).

DOI: 10.1016/0140-6736(90)91518-F

◆     Suggests a link between BSE (mad cow disease) and human prion diseases. This paper went out prior to any major problems with humans eating contaminated meat, and indicates a possibility that BSE might be able to be transmitted to humans.


➔      Zahn, R. et al. NMR solution structure of the human prion protein. Proceedings of the National Academy of Sciences 97, 145–150 (2000).

DOI: 10.1073/pnas.97.1.145

◆     One of the earliest structures of the full version of human PRNP. This paper offers a remarkably penetrating analysis of the structure, comparing it to different species, and noting that the differences in structures are centered primarily around portions of the protein where previous research has suggested protein-protein interactions may occur. The paper suggests that these regions may be important in trans-species infectivity and immune reactions to foreign PRNP.


➔      Knaus, K. et al. Crystal structure of the human prion protein reveals a mechanism for oligomerization. Nature Stuctural Biology 770–774 (2001).

DOI: 10.1038/nsb0901-770

◆     In an unfortunate turn of events for the authors of the previous paper in this list, these authors are able to more powerfully synthesize data from their structure (crystallographers:1, NMR specialists:0 ?). These authors use a truncated form of the protein to show that dimers are formed by normal PRNP, and this is confirmed by SDS-PAGE. The authors are also able to extend this information into a potential method by which misfolded PRNP interacts with wild-type protein to “convert” it. The authors are thorough in their work and uncover a number of significant points about the structure of the dimer and how the interactions may occur.


➔      Sanchez-Juan, P. et al. Genome-wide study links MTMR7 gene to variant Creutzfeldt-Jakob risk. Neurobiology of Aging 33, 1487.e21–1487.e28 (2012).

DOI: 10.1016/j.neurobiolaging.2011.10.011

◆     The authors here link two loci other than PrP to CJD susceptibility. Their discoveries uncover what they believe to be a significant metabolic link between the other genetic loci and the downstream effects of CJD. MTMR7 is a protein involved in long-term memory in the CNS, which is severely impaired in CJD.


➔      Criado, J. R. et al. Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiology of Disease 19, 255–265 (2005).

DOI: 10.1016/j.nbd.2005.01.001

◆     In this paper the authors do functional and behavioral studies in mice which aim to discover the normal function of the prion protein. They implicate PrP in long-term memory as tested by spatial memory tests in knockout mice. The mice devoid of prion protein had no ability to remember the layout of a maze, which was rescued by a time-dependent switch restoring PrP expression.


➔      Tobler, I. et al. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380, 639–642 (1996).

DOI: 10.1038/380639a0

◆     This paper also exposes some of the functional roles of PrP which is known to be expressed primarily in the CNS. Here, the authors show that sleep patterns of mice devoid of PRNP are greatly altered. This is the main phenotype of another prion disease in humans, fatal familial insomnia.


➔      Papassotiropoulos, A. The prion gene is associated with human long-term memory. Human Molecular Genetics 14, 2241–2246 (2005).

DOI: 10.1093/hmg/ddi228

◆     Here the authors find a link in human students tested for long-term word recall. Students were screened genetically and their results were matched up with their performance on long-term recall tests. A certain polymorphism at amino acid 129 was correlated with a 17% increase in a student’s ability to recall words in the long-term. Short term memory tests, however, did not show any such correlation. Given the drastic cognitive effects of CJD, it is not a surprise that the natural role of PrP might be in long term memory.


➔      Kong, Q. et al. Thermodynamic Stabilization of the Folded Domain of Prion Protein Inhibits Prion Infection in Vivo. Cell Reports 4, 248–254 (2013).

DOI: 10.1016/j.celrep.2013.06.030

◆     Remarkably, researchers are able to introduce a stabilizing mutation into human PRNP at position 209. The stability of this alpha-helix is confirmed by calorimetry, and it confers a strong resistance to infection with pathogenic PRNP. These results begin to shed light on the actual methods of conversion of normal PRNP to pathogenic PRNP, which is not very well understood. It makes suggestions as to possible treatment options.


➔      Cai, H., Xie, Y., Hu, L., Fan, J. & Li, R. Prion protein (PrPc) interacts with histone H3 confirmed by affinity chromatography. Journal of Chromatography B 929, 40–44 (2013).

DOI: 10.1016/j.jchromb.2013.04.003

◆     Here, the authors find a startling relationship between H3 and PRNP (they call it PrPc). Although the interaction found was only in vitro, on a column, it does not escape my notice that this would coincide with Kaski et al.’s suggestion that an overexpression of PRNP may be part of the pathogenesis of CJD, since histone modification can lead to down or up regulation of proteins. The authors also make a small mention near the end of their paper that they believe that Sirtuins may also be involved somehow, though they give sparse evidence for this claim.


➔      Soldevila, M. The prion protein gene in humans revisited: Lessons from a worldwide resequencing study. Genome Research 16, 231–239 (2005).

DOI: 10.1101/gr.4345506

◆     This large “-omic” study confirms the correlation between certain haplotypes, the mutation of residue 129, and CJD susceptibility. They also indicate that the variation of PRNP sequences among the world population is abnormal, or not what would be expected. They find that there is evidence of purifying or positive selection on PRNP over time.


➔      Armstrong, R. ., Lantos, P. . & Cairns, N. . The spatial patterns of prion protein deposits in Creutzfeldt–Jakob disease: comparison with β-amyloid deposits in Alzheimer’s disease. Neuroscience Letters 298, 53–56 (2001).

DOI: 10.1016/S0304-3940(00)01725-0

◆     The authors of this paper compare deposits of protein aggregates in CJD and Alzheimers, PRNP in CJD and beta-amyloid in Alzheimers. Similarities existed between distribution of deposits, and progression of pathologies. However, brain regions affected by these plaques were different between the two diseases. Still, the article indicates an interesting correlation where one disease may yet be useful in researching the other.


➔      Tian, H., Zhang, J., Lang, S. & Wang, X. MRI sequence findings in sporadic Creutzfeldt–Jakob disease. Journal of Clinical Neuroscience 17, 1378–1380 (2010).

DOI: 10.1016/j.jocn.2010.03.032

◆     The authors herein provide a possible basis for diagnosing CJD via MRI tests. They review some current diagnostics and compare them to MRI. This is useful in that it is one of the stronger tests for CJD, which has very little by way of diagnosis and less by way of treatment


➔      Bishop, M. T. et al. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt-Jakob disease. Brain 136, 1139–1145 (2013).

DOI: 10.1093/brain/awt032

◆     The authors here detail a case where an M/V heterozygote at the 129 position on PRNP was “infected” by a blood transfusion from a CJD-positive individual. The prions were found in his lymph and in his spleen, but not in his brain. The authors wonder whether to consider this subclinical version of the prion’s presence “infection”, given that all other variant CJD cases have been in M/M homozygotes at the 129 position

➔      Head, M. W. & Ironside, J. W. The contribution of different prion protein types and host polymorphisms to clinicopathological variations in Creutzfeldt-Jakob disease: Phenotypic variation in CJD. Reviews in Medical Virology 22, 214–229 (2012).

DOI: 10.1002/rmv.725

◆     This paper reviews numerous pieces of the literature and attempts to make an argument about the extremely varied phenotypes in CJD. The authors indicate that a patient’s genetics, including but not limited to their particular mutations (or lack thereof) in PrP as well as the epigenetic aspects of the prion. However, they complicate the issue and propose better ways of looking at CJD risk and the eventual severity of the disease, as well as its ability to progress.



➔      Jakob A: Über eigenartige Erkrankungen des Zentralnervensystems mit bemerkenswerten anatomischen Befunden (spastische Pseudosklerose-Encephalomyelopathie mit disseminierten Degenerationsherden). Z Ges Neurol Psychiatr 1921;64:147–228.

➔      Creutzfeldt H: Über eine eigenartige herdförmige Erkrankung des Zentralnervensystems. Z Ges Neurol Psychiatr 1920;57:1–18

No DOI available!

◆     These studies were the first two to identify what we now know to have been CJD. The cases are described as disseminated encephalomyelopathies. There is no DOI data available for these papers because they are in german and were published in the 20s.


➔      Johnson, R. T. & Gibbs, C. J. Creutzfeldt–Jakob Disease and Related Transmissible Spongiform Encephalopathies. New England Journal of Medicine 339, 1994–2004 (1998).


◆     Description of symptoms and characterizations of CJD phenotypes. Also relates to other TSEs.


➔      Gajdusek, D. C. & Zigas, V. Degenerative Disease of the Central Nervous System in New Guinea: The Endemic Occurrence of Kuru in the Native Population. New England Journal of Medicine 257, 974–978 (1957).


◆     Gajdusek’s discoveries concerning Kuru and Scrapie. This work would eventually lead to his connections between CJD, Kuru and Scrapie and to an important experiment in the CJD story.


➔      Gibbs, C. J. et al. Creutzfeldt-Jakob Disease (Spongiform Encephalopathy): Transmission to the Chimpanzee. Science 161, 388–389 (1968).

DOI: 10.1126/science.161.3839.388

➔      Gajdusek, D. C., Gibbs, C. J. & Alpers, M. Experimental Transmission of a Kuru-like Syndrome to Chimpanzees. Nature 209, 794–796 (1966).

DOI: 10.1038/209794a0

◆     Landmark studies showing the infection of chimpanzees with brain matter from CJD and Kuru and thus the transmissibility of these TSEs.


➔      Jackson, G. S. et al. A highly specific blood test for vCJD. Blood 123, 452–453 (2014). DOI: 10.1182/blood-2013-11-539239

◆     Development of a fairly reliable blood test for CJD. This is one of the first diagnostic tests for the disease even since 82’ when it first became fairly widely accepted that a prion was responsible for CJD’s pathogenesis.


➔      Wisniewski, T. & Goñi, F. Could immunomodulation be used to prevent prion diseases? Expert Review of Anti-infective Therapy 10, 307–317 (2012). DOI:10.1586/eri.11.177

◆     Discusses potential immuno responses for prion diseases. Treatment options? Or just a preventative matter?


➔      Korth, C. & Peters, P. J. Emerging Pharmacotherapies for Creutzfeldt-Jakob Disease. Archives of Neurology 63, 497 (2006).

DOI: 10.1001/archneur.63.4.497

◆     Discusses different therapies for CJD, good section on RNAi. Lists pros and cons for some of the therapies as well.