PRNP
Major prion protein precursor (PrP) (ASCR) (PrP27-30) (PrP33-35C) (CD230 antigen) [ALTPRP] [PRIP] [PRP]
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Inherited prion diseases are caused by autosomal dominant coding mutations in the human prion protein (PrP) gene ([[PRNP]]) and account for about 15% of human prion disease cases worldwide. The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis, to-date spontaneous formation of disease-relevant, transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Here, we report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which model the [[PRNP]] A117V mutation causing inherited prion disease (IPD) including Gerstmann-Sträussler-Scheinker (GSS) disease phenotypes in humans. By studying brain samples from uninoculated groups of mice, we discovered that some mice (≥475 days old) spontaneously generated abnormal PrP assemblies, which after inoculation into further groups of 117VV Tg30 mice, produced a molecular and neuropathological phenotype congruent with that seen after transmission of brain isolates from IPD A117V patients to the same mice. To the best of our knowledge, the 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited prion disease in humans.
MeSH Terms
- Adult
- Aging
- Amyloid
- Animals
- Brain
- Codon
- Heterozygote
- Homozygote
- Humans
- Mice, Transgenic
- Middle Aged
- Prions
Biopsy of rectal mucosa-associated lymphoid tissue provides a useful, but imperfect, live-animal test for chronic wasting disease (CWD) in mule deer (Odocoileus hemionus). It is difficult and expensive to complete these tests on free-ranging animals, and wildlife health managers will benefit from methods that can accommodate test results of varying quality. To this end, we developed a hierarchical Bayesian model to estimate the probability that an individual is infected based on test results. Our model was estimated with the use of data on 210 adult female mule deer repeatedly tested during 2010-14. The ability to identify infected individuals correctly declined with age and may have been influenced by repeated biopsy. Fewer isolated lymphoid follicles (where PrP(CWD) accumulates) were obtained in biopsies of older deer and the proportion of follicles showing PrP(CWD) was reduced. A deer's genotype in the prion gene ([[PRNP]]) also influenced detection. At least five follicles were needed in a biopsy to assure a 95% accurate test in [[PRNP]] genotype 225SS deer.
MeSH Terms
- Aging
- Animals
- Animals, Wild
- Bayes Theorem
- Biopsy
- Colorado
- Deer
- Female
- Genetic Predisposition to Disease
- Genotype
- Lymphoid Tissue
- Models, Biological
- Prions
- Wasting Disease, Chronic
Keywords
- Bayesian
- capture–mark–recapture
- chronic wasting disease
- mule deer
- prion
- test sensitivity
The [[PRNP]] gene encodes the cellular isoform of prion protein (PrP (c) ). The M129V polymorphism influences the risk of prion diseases and may modulate the rate of neurodegeneration with age. We present the first study of the polymorphism among Polish centenarians. In the control group (n = 165, ages 18 to 56 years) the observed M129V genotype frequencies agreed with those expected according to the Hardy-Weinberg equilibrium (MM, MV, VV): 43%, 44%, 13% (HWE p > 0.05). Among centenarians (n = 150, ages 100 to 107) both homozygotes were more common than expected and HWE was rejected: 46%, 37%, 17% (expected 42%, 46%, 13%; HWE p = 0.025). This finding is consistent with a higher mortality rate among heterozygotes. However, the observed allele and genotype frequencies did not differ significantly between the oldest-old and the young controls. The genotypic frequencies were not related to severe cognitive impairment among the centenarians.
MeSH Terms
- Adolescent
- Adult
- Aged, 80 and over
- Cognition Disorders
- European Continental Ancestry Group
- Female
- Homozygote
- Humans
- Longevity
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Prions
- Young Adult
Keywords
- M129V
- PRNP
- centenarians
- codon 129 polymorphism
- cognitive impairment
- genetic epidemiology
- longevity
- selective mortality