Nobel Lecture: Prions

Prions cause transmissible and genetic neurodegenerative diseases, including scrapie and bovine spongiform encephalopathy of animals and Creutzfeldt-Jakob and Gerstmann-Straussler-Scheinker diseases of humans. Infectious prion particles are composed largely, if not entirely, of an abnormal isoform of the prion protein, which is encoded by a chromosomal gene. A posttranslational process, as yet unidentified, converts the cellular prion protein into an abnormal isoform. Scrapie incubation times, neuropathology, and prion synthesis in transgenic mice are controlled by the prion protein gene. Point mutations in the prion protein genes of animals and humans are genetically linked to development of neuro-degeneration. Transgenic mice expressing mutant prion proteins spontaneously develop neurologic dysfunction and spongiform neuropathology. Understanding prion diseases may advance investigations of other neurodegenerative disorders and of the processes by which neurons differentiate, function for decades, and then grow senescent.

https://science.sciencemag.org/content/sci/252/5012/1515.full.pdf

Molecular biology of prion diseases

▪ Abstract Prion diseases are transmissible neurodegenerative conditions that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals. Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein. Prion propagation involves recruitment of host cellular prion protein, composed primarily of α-helical structure, into a disease specific isoform rich in β-sheet structure. The existence of multiple prion strains has been difficult to explain in terms of a protein-only infections agent, but recent studies suggest that strain specific phenotypes can be encoded by different prion protein conformations and glycosylation patterns. The ability of a protein to encode phenotypic information has important biological implications. The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the ...

Prion Diseases of Humans and Animals: Their Causes and Molecular Basis

Recombinant mouse prion protein (recMoPrP) produced in Escherichia coli was polymerized into amyloid fibrils that represent a subset of beta sheet-rich structures. Fibrils consisting of recMoPrP(89-230) were inoculated intracerebrally into transgenic (Tg) mice expressing MoPrP(89-231). The mice developed neurologic dysfunction between 380 and 660 days after inoculation. Brain extracts showed protease-resistant PrP by Western blotting; these extracts transmitted disease to wild-type FVB mice and Tg mice overexpressing PrP, with incubation times of 150 and 90 days, respectively. Neuropathological findings suggest that a novel prion strain was created. Our results provide compelling evidence that prions are infectious proteins.

https://science.sciencemag.org/content/sci/305/5684/673.full.pdf

Synthetic Mammalian Prions

Prion and nonprion forms of proteins are believed to differ solely in their three-dimensional structure, which is therefore of paramount importance for the prion function. However, no atomic-resolution structure of the fibrillar state that is likely infectious has been reported to date. We present a structural model based on solid-state nuclear magnetic resonance restraints for amyloid fibrils from the prion-forming domain (residues 218 to 289) of the HET-s protein from the filamentous fungus Podospora anserina. On the basis of 134 intra- and intermolecular experimental distance restraints, we find that HET-s(218–289) forms a left-handed β solenoid, with each molecule forming two helical windings, a compact hydrophobic core, at least 23 hydrogen bonds, three salt bridges, and two asparagine ladders. The structure is likely to have broad implications for understanding the infectious amyloid state.

Amyloid fibrils of the HET-s(218–289) prion form a β-solenoid with a triangular hydrophobic core.

A novel progressive spongiform encephalopathy in cattle.

In recent history, access to biological and genomic data (provided by DNA sequencing) has exponentially increased as more efficient technologies have been developed. Newer, more accurate algorithms for analyzing this data are in high demand: in particular, the search for relatedness amongst individuals in a population to detect deleterious mutations that predispose one to certain diseases. Genome-wide association studies (GWAS) search for these disease-causing mutations, and motivation for this thesis is to improve identification and tracing of these mutations. Identity by descent (IBD)—segments of DNA shared between individuals sharing a common ancestor—is a principle that can be used to detect genetic variants and estimate mutation rates (Zhou et al., 2020). Several algorithmic methods can be utilized to pinpoint regions of IBD in genomic data: GERMLINE (used for thread , an algorithm that can reconstruct the genomes of ancestors via tracing IBD segments back through a pedigree), hap-IBD, and templated positional Burrows-Wheeler transform (TPBWT) will be the main focal points of this thesis. These methods use different tactics to find IBD segments such as “seed-and-extend” of IBS regions—small, shared segments of nucleotides—as for hap-IBD and GERMLINE (Zhou et al., 2020), or using an improved PBWT and heuristic algorithm to stitch together the IBD segments in TPBWT. All methods struggle to control levels of error introduced through handling genomic data. False negative and false positive errors are nearly inescapable despite the best efforts of contemporary algorithms. Therefore, one might consider using a pedigree—a tree-like diagram depicting the relationships between several generations of family members—to reduce the likelihood of these errors. These pedigrees, armed with the ability to show true relatedness, can be applied to algorithmically determined IBD segments to check if the amount of IBD sharing between pairs of individuals is realistic given their genealogical relationship. A comparison between these IBD identification algorithms will provide insight into what methods will provide consistent results long-term as GWAS data continues to increase. The foremost of these algorithms could then be combined with pedigrees to further bolster accuracy and efficiency of IBD detection. We endeavor This article provides a quality overview of how pedigrees can be used to analyze heritability in a schizophrenia-affected population and locate linkage disequilibrium, which occurs when linked alleles are partitioned nonrandomly on the same chromosome. Non-algorithmic procedures were used to determine the IBD regions within the schizophrenia-affected individuals related 12 generations past on the pedigree. This article will be used for general information regarding pedigrees and how they have been previously used to determine IBD.

C.T. Johnson

Papers

A novel progressive spongiform encephalopathy in cattle.

Comparison of Identity by Descent Detection Algorithms and their Implementation with Pedigrees