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John Collinge - One of the best experts on this subject based on the ideXlab platform.

  • Prion Disease
    New Oxford Textbook of Psychiatry, 2020
    Co-Authors: Akin Nihat, Tzehow Mok, John Collinge
    Abstract:

    Prion Diseases are fatal neurodegenerative conditions that may arise sporadically or be inherited or acquired by environmental exposure to infectious Prions—transmissible agents composed of multimeric assemblies of misfolded protein. The core clinical features are progressive cognitive decline, accompanied with ataxia, myoclonus, and pyramidal or extra-pramidal motor signs. While the most common form—sporadic Creutzfeldt–Jakob Disease—is generally rapidly progressive over weeks or months, inherited Prion Diseases can span many years, with diverse clinical features readily mimicking other neurodegenerative Diseases. Psychiatric features, including agitation, anxiety, depression, hallucinations, and behavioural disturbances, are common in the early stages. Diagnosis can usually be made with confidence by the combination of clinical criteria, diffusion-weighted magnetic resonance imaging, electroencephalogram, and specialized cerebrospinal fluid analysis. Inherited Prion Disease can be confirmed with Prion protein gene analysis, which should be considered in all early-onset dementing and ataxic conditions. It is now becoming clear that the fundamental molecular pathogenesis—seeded protein polymerization—is relevant to other neurodegenerative Diseases, notably Alzheimer’s Disease.

  • ascertainment bias causes false signal of anticipation in genetic Prion Disease
    American Journal of Human Genetics, 2014
    Co-Authors: Eric Vallabh Minikel, Inga Zerr, Steven J Collins, Claudia Ponto, Alison Boyd, Genevieve M Klug, Andre Karch, Joanna Kenny, John Collinge
    Abstract:

    Anticipation is the phenomenon whereby age of onset in genetic Disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob Disease (CJD) caused by the c.598G>A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the Prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four Prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation’s 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose Disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic Prion Disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.

  • Microglial Cx3cr1 knockout reduces Prion Disease incubation time in mice.
    BMC Neuroscience, 2014
    Co-Authors: Julia Grizenkova, Shaheen Akhtar, Sebastian Brandner, John Collinge, Sarah E. Lloyd
    Abstract:

    Background Microglia are resident mononuclear phagocytes of the brain that become activated in response to insults including neurodegenerative Diseases such as Alzheimer’s Disease, Parkinson’s Disease and Prion Disease. In the central nervous system the chemokine Cx3cl1 (Fractalkine) is expressed by neurons and its exclusive receptor Cx3cr1 is expressed solely on microglia. Cx3cl1/Cx3cr1 signalling is thought to maintain microglia in their resting state and disrupting this equilibrium may allow microglia to become activated. In Prion Disease, microglial proliferation has been suggested to contribute to overall Disease progression, however, in different mouse models of neurodegeneration, loss of Cx3cr1 has been shown to either worsen or improve the phenotype depending on the paradigm.

  • age of onset and death in inherited Prion Disease are heritable
    American Journal of Medical Genetics, 2009
    Co-Authors: T Webb, John Collinge, John C Whittaker, Simon Mead
    Abstract:

    The common polymorphism at codon 129 of the Prion protein gene (PRNP) is known to affect Prion Disease susceptibility, incubation period and phenotype. Mouse quantitative trait locus (QTL) studies demonstrate multiple modifiers of incubation time unlinked to Prnp, suggesting the existence of homologous human Prion Disease modifiers, but direct evidence of these has been lacking. We investigated the correlation of age at onset and death, expressed as a composite Z score, between parents and offspring in three large UK inherited Prion Disease kindreds. Our analysis suggests that overall heritability of the composite phenotype is 0.55 (95% CI 0.35-0.75). This measure may be an underestimate of the total genetic contribution to phenotypic heterogeneity as the analysis does not incorporate the effect of PRNP-linked modifiers. Although the confidence intervals are wide, these data suggest a significant heritable component to phenotypic variability and support attempts to identify human Prion Disease modifier genes which would be important in understanding the epidemiology of variant Creutzfeldt-Jakob Disease (vCJD) in populations with significant exposure to bovine spongiform encephalopathy (BSE) Prions.

  • safety and efficacy of quinacrine in human Prion Disease Prion 1 study a patient preference trial
    Lancet Neurology, 2009
    Co-Authors: John Collinge, Michele Gorham, Fleur Hudson, A M Kennedy, Geraldine Keogh, Martin N Rossor, Peter Rudge, Durre Siddique
    Abstract:

    Summary Background The propagation of Prions, the causative agents of Creutzfeldt-Jakob Disease and other human Prion Diseases, requires post-translational conversion of normal cellular Prion protein to Disease-associated forms. The antimalarial drug quinacrine (mepacrine) prevents this conversion in vitro, and was given to patients with various Prion Diseases to assess its safety and efficacy in changing the course of these invariably fatal and untreatable Diseases. Methods Patients with Prion Disease were recruited via the UK national referral system and were offered a choice between quinacrine (300 mg daily), no quinacrine, or randomisation to immediate quinacrine or deferred quinacrine in an open-label, patient-preference trial. The primary endpoints were death and serious adverse events possibly or probably related to the study drug. This study is registered, ISRCTN 06722585. Findings 107 patients with Prion Disease (45 sporadic, two iatrogenic, 18 variant, and 42 inherited) were enrolled, 23 in a pilot study and 84 in the main study. Only two patients chose randomisation; 40 took quinacrine during follow-up (37 who chose it at enrolment). Choice of treatment was associated with Disease severity, with those least and most severely affected more likely to choose not to receive quinacrine. 78 (73%) patients died: one randomly assigned to deferred treatment, 26 of 38 who chose immediate quinacrine, and 51 of 68 who chose no quinacrine. Although adjusted mortality was lower in those who chose to take quinacrine than in those who did not, this was due to confounding with Disease severity, and there was no difference in mortality between groups after adjustment. Four of 40 patients who took quinacrine had a transient response on neurological rating scales. Only two of 14 reported serious adverse events were judged quinacrine-related. Interpretation Quinacrine at a dose of 300 mg per day was reasonably tolerated but did not significantly affect the clinical course of Prion Diseases in this observational study. Funding Department of Health (England); UK Medical Research Council.

Eric Vallabh Minikel - One of the best experts on this subject based on the ideXlab platform.

  • Prion protein lowering is a Disease modifying therapy across Prion Disease stages strains and endpoints
    Nucleic Acids Research, 2020
    Co-Authors: Eric Vallabh Minikel, Rose Pitstick, Hien Zhao, Jill Omoore, Samantha Graffam, George A Carlson, Michael P Kavanaugh, Jasna Kriz, Jae Beom Kim, Holger Wille
    Abstract:

    Lowering of Prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in Prion Disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays Disease onset in intracerebrally Prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, Prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional Prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against Prion Disease.

  • Prion protein lowering is a Disease modifying therapy across Prion Disease stages strains and endpoints
    bioRxiv, 2020
    Co-Authors: Eric Vallabh Minikel, Rose Pitstick, Hien Zhao, Jill Omoore, Samantha Graffam, George A Carlson, Michael P Kavanaugh, Jasna Kriz, Jae Beom Kim, Holger Wille
    Abstract:

    Abstract Lowering of Prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in Prion Disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays Disease onset in intracerebrally Prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, Prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional Prion strains. We demonstrate that less than 25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against Prion Disease.

  • cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic Prion Disease
    BMC Medicine, 2020
    Co-Authors: Sonia M Vallabh, Eric Vallabh Minikel, Victoria J Williams, Becky C Carlyle, Alison J Mcmanus, Chase D Wennick, Anna Bolling, Bianca A Trombetta, David Urick, Chloe K Nobuhara
    Abstract:

    Prion Disease is neurodegenerative Disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic Prion Disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic Prion Disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with Prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total Prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) Prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2–4 months, and conducted a pilot longitudinal study over 10–20 months. CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2–4 months in N = 29 participants and over 10–20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of Prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for Prion Disease advance, “secondary prevention” based on prodromal pathology may prove challenging; instead, “primary prevention” trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.

  • Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic Prion Disease
    BMC Medicine, 2020
    Co-Authors: Sonia M Vallabh, Eric Vallabh Minikel, Victoria J Williams, Becky C Carlyle, Alison J Mcmanus, Chase D Wennick, Anna Bolling, Bianca A Trombetta, David Urick, Chloe K Nobuhara
    Abstract:

    Background Prion Disease is neurodegenerative Disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic Prion Disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic Prion Disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. Methods We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with Prion protein gene ( PRNP ) mutations ( N  = 27) and matched controls ( N  = 16), in a cohort study at Massachusetts General Hospital. We quantified total Prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) Prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2–4 months, and conducted a pilot longitudinal study over 10–20 months. Results CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2–4 months in N  = 29 participants and over 10–20 months in N  = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. Conclusions CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of Prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for Prion Disease advance, “secondary prevention” based on prodromal pathology may prove challenging; instead, “primary prevention” trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.

  • towards a treatment for genetic Prion Disease trials and biomarkers
    Lancet Neurology, 2020
    Co-Authors: Eric Vallabh Minikel, Sonia M Vallabh, Stuart L Schreiber, Eric S Lander
    Abstract:

    Prion Disease is a rare, fatal, and exceptionally rapid neurodegenerative Disease. Although incurable, Prion Disease follows a clear pathogenic mechanism, in which a single gene gives rise to a single Prion protein (PrP) capable of converting into the sole causal Disease agent, the misfolded Prion. As efforts progress to leverage this mechanistic knowledge toward rational therapies, a principal challenge will be the design of clinical trials. Previous trials in Prion Disease have been done in symptomatic patients who are often profoundly debilitated at enrolment. About 15% of Prion Disease cases are genetic, creating an opportunity for early therapeutic intervention to delay or prevent Disease. Highly variable age of onset and absence of established prodromal biomarkers might render infeasible existing models for testing drugs before Disease onset. Advancement of near-term targeted therapeutics could crucially depend on thoughtful design of rigorous presymptomatic trials.

Claudio Soto - One of the best experts on this subject based on the ideXlab platform.

  • efficient Prion Disease transmission through common environmental materials
    Journal of Biological Chemistry, 2018
    Co-Authors: Sandra Pritzkow, Rodrigo Morales, Adam Lyon, Luis Conchamarambio, Akihiko Urayama, Claudio Soto
    Abstract:

    Prion Diseases are a group of fatal neurodegenerative Diseases associated with a protein-based infectious agent, termed Prion. Compelling evidence suggests that natural transmission of Prion Diseases is mediated by environmental contamination with infectious Prions. We hypothesized that several natural and man-made materials, commonly found in the environments of wild and captive animals, can bind Prions and may act as vectors for Disease transmission. To test our hypothesis, we exposed surfaces composed of various common environmental materials (i.e. wood, rocks, plastic, glass, cement, stainless steel, aluminum, and brass) to hamster-adapted 263K scrapie Prions and studied their attachment and retention of infectivity in vitro and in vivo. Our results indicated that these surfaces, with the sole exception of brass, efficiently bind, retain, and release Prions. Prion replication was studied in vitro using the protein misfolding cyclic amplification technology, and infectivity of surface-bound Prions was analyzed by intracerebrally challenging hamsters with contaminated implants. Our results revealed that virtually all Prion-contaminated materials transmitted the Disease at high rates. To investigate a more natural form of exposure to environmental contamination, we simply housed animals with large contaminated spheres made of the different materials under study. Strikingly, most of the hamsters developed classical clinical signs of Prion Disease and typical Disease-associated brain changes. Our findings suggest that Prion contamination of surfaces commonly present in the environment can be a source of Disease transmission, thus expanding our understanding of the mechanisms for Prion spreading in nature.

  • treatment with a non toxic self replicating anti Prion delays or prevents Prion Disease in vivo
    Molecular Psychiatry, 2018
    Co-Authors: Rodrigo Diazespinoza, Rodrigo Morales, Luis Conchamarambio, Claudio Soto, Ines Morenogonzalez, Fabio Moda
    Abstract:

    Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders caused by Prions, which are composed of a misfolded protein (PrPSc) that self-propagates in the brain of infected individuals by converting the normal Prion protein (PrPC) into the pathological isoform. Here, we report a novel experimental strategy for preventing Prion Disease based on producing a self-replicating, but innocuous PrPSc-like form, termed anti-Prion, which can compete with the replication of pathogenic Prions. Our results show that a prophylactic inoculation of Prion-infected animals with an anti-Prion delays the onset of the Disease and in some animals completely prevents the development of clinical symptoms and brain damage. The data indicate that a single injection of the anti-Prion eliminated ~99% of the infectivity associated to pathogenic Prions. Furthermore, this treatment caused significant changes in the profile of regional PrPSc deposition in the brains of animals that were treated, but still succumbed to the Disease. Our findings provide new insights for a mechanistic understanding of Prion replication and support the concept that Prion replication can be separated from toxicity, providing a novel target for therapeutic intervention.

Ilia V. Baskakov - One of the best experts on this subject based on the ideXlab platform.

  • Two alternative pathways for generating transmissible Prion Disease de novo
    Acta Neuropathologica Communications, 2015
    Co-Authors: Natallia Makarava, Regina Savtchenko, Ilia V. Baskakov
    Abstract:

    Introduction Previous studies established that Prion Disease with unique strain-specific phenotypes could be induced by in vitro -formed recombinant PrP (rPrP) fibrils with structures different from that of authentic Prions, or PrP^Sc. To explain the etiology of Prion Diseases, new mechanism proposed that in animals the transition from rPrP fibrils to PrP^Sc consists of two main steps: the first involves fibril-induced formation of atypical PrPres, a self-replicating but clinically silent state, and the second consists of atypical PrPres-dependent formation of PrP^Sc via rare deformed templating events. Results In the current study, atypical PrPres with characteristics similar to those of brain-derived atypical PrPres was generated in vitro . Upon inoculation into animals, in vitro -generated atypical PrPres gave rise to PrP^Sc and Prion Disease with a phenotype similar to those induced by rPrP fibrils. Significant differences in the sialylation pattern between atypical PrPres and PrP^Sc suggested that only a small sub-fraction of the PrP^C that is acceptable as a substrate for PrP^Sc could be also recruited by atypical PrPres. This can explain why atypical PrPres replicates slower than PrP^Sc and why PrP^Sc outcompetes atypical PrPres. Conclusions This study illustrates that transmissible Prion Diseases with very similar Disease phenotypes could be produced via two alternative procedures: direct inoculation of recombinant PrP amyloid fibrils or in vitro -produced atypical PrPres. Moreover, this work showed that preparations of atypical PrPres free of PrP^Sc can give rise to transmissible Diseases in wild type animals and that atypical PrPres generated in vitro is an adequate model for brain-derived atypical PrPres.

  • genesis of mammalian Prions from non infectious amyloid fibrils to a transmissible Prion Disease
    PLOS Pathogens, 2011
    Co-Authors: Natallia Makarava, Gabor G. Kovacs, Regina Savtchenko, Irina Alexeeva, Herbert Budka, Robert G. Rohwer, Ilia V. Baskakov
    Abstract:

    The transmissible agent of Prion Disease consists of a Prion protein in its abnormal, β-sheet rich state (PrPSc), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrPSc template. Here we report that authentic PrPSc and transmissible Prion Disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrPSc and lack any detectable PrPSc particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical Disease. Once emerged, the Prion Disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the Disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres) before authentic PrPSc evolved. The current work illustrates that transmissible Prion Diseases can be induced by PrP structures different from that of authentic PrPSc and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as “deformed templating” postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrPSc can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative Diseases.

  • Recombinant Prion protein induces a new transmissible Prion Disease in wild-type animals
    Acta Neuropathologica, 2010
    Co-Authors: Natallia Makarava, Gabor G. Kovacs, Olga Bocharova, Regina Savtchenko, Irina Alexeeva, Herbert Budka, Robert G. Rohwer, Ilia V. Baskakov
    Abstract:

    Prion Disease is a neurodegenerative malady, which is believed to be transmitted via a Prion protein in its abnormal conformation (PrP^Sc). Previous studies have failed to demonstrate that Prion Disease could be induced in wild-type animals using recombinant Prion protein (rPrP) produced in Escherichia coli . Here, we report that Prion infectivity was generated in Syrian hamsters after inoculating full-length rPrP that had been converted into the cross-β-sheet amyloid form and subjected to annealing. Serial transmission gave rise to a Disease phenotype with highly unique clinical and neuropathological features. Among them were the deposition of large PrP^Sc plaques in subpial and subependymal areas in brain and spinal cord, very minor lesioning of the hippocampus and cerebellum, and a very slow progression of Disease after onset of clinical signs despite the accumulation of large amounts of PrP^Sc in the brain. The length of the clinical duration is more typical of human and large animal Prion Diseases, than those of rodents. Our studies establish that transmissible Prion Disease can be induced in wild-type animals by inoculation of rPrP and introduce a valuable new model of Prion Diseases.

Elizabeth M C Fisher - One of the best experts on this subject based on the ideXlab platform.

  • overexpression of the hspa13 stch gene reduces Prion Disease incubation time in mice
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Julia Grizenkova, Shaheen Akhtar, Holger Hummerich, Andrew Tomlinson, Emmanuel A Asante, Adam Wenborn, Jeremie Fizet, M Poulter, Frances K Wiseman, Elizabeth M C Fisher
    Abstract:

    Prion Diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob Disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in Prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) Prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 Prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as Prion Disease.

  • identification of multiple quantitative trait loci linked to Prion Disease incubation period in mice
    Proceedings of the National Academy of Sciences of the United States of America, 2001
    Co-Authors: S E Lloyd, John Collinge, Obia N Onwuazor, Jonathan Beck, Gary Mallinson, Martin Farrall, Paul V Targonski, Elizabeth M C Fisher
    Abstract:

    Polymorphisms in the Prion protein gene are known to affect Prion Disease incubation times and susceptibility in humans and mice. However, studies with inbred lines of mice show that large differences in incubation times occur even with the same amino acid sequence of the Prion protein, suggesting that other genes may contribute to the observed variation. To identify these loci we analyzed 1,009 animals from an F2 intercross between two strains of mice, CAST/Ei and NZW/OlaHSd, with significantly different incubation periods when challenged with RML scrapie Prions. Interval mapping identified three highly significantly linked regions on chromosomes 2, 11, and 12; composite interval mapping suggests that each of these regions includes multiple linked quantitative trait loci. Suggestive evidence for linkage was obtained on chromosomes 6 and 7. The sequence conservation between the mouse and human genome suggests that identification of mouse Prion susceptibility alleles may have direct relevance to understanding human susceptibility to bovine spongiform encephalopathy (BSE) infection, as well as identifying key factors in the molecular pathways of Prion pathogenesis. However, the demonstration of other major genetic effects on incubation period suggests the need for extreme caution in interpreting estimates of variant Creutzfeldt-Jakob Disease epidemic size utilizing existing epidemiological models.