Mapping the prion protein distribution in marsupials: insights from comparing opossum with mouse CNS

The cellular form of the prion protein (PrP(C)) is a sialoglycoprotein widely expressed in the central nervous system (CNS) of mammalian species during neurodevelopment and in adulthood. The location of the protein in the CNS may play a role in the susceptibility of a species to fatal prion diseases, which are also known as the transmissible spongiform encephalopathies (TSEs). To date, little is known about PrP(C) distribution in marsupial mammals, for which no naturally occurring prion diseases have been reported. To extend our understanding of varying PrP(C) expression profiles in different mammals we carried out a detailed expression analysis of PrP(C) distribution along the neurodevelopment of the metatherian South American short-tailed opossum (Monodelphis domestica). We detected lower levels of PrP(C) in white matter fiber bundles of opossum CNS compared to mouse CNS. This result is consistent with a possible role for PrP(C) in the distinct neurodevelopment and neurocircuitry found in marsupials compared to other mammalian species

Genetic Predictions of Prion Disease Susceptibility in Carnivore Species Based on Variability of the Prion Gene Coding Region

Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrP(C)) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrP(C) protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter

Early diagnosis of human TSE by multimodality MRI: Spectroscopic detection of thalamic gliosis in a patient with FFI and normal FLAIR and diffusion-weighted imaging

International audienceRecently, several reports underlined the usefulness of brain MRI for the diagnosis ofCreutzfeldt-Jakob dis ease. FLAIR sequence and diffusion-weighted imaging (DWI) areconsidered as high sensitive sequences to detect signal alteration of the cortex and thedeep grey matter. Recent advances in therapeutic approach of patients with prion diseaseshave emphasized the need for earlier diagnostic markers that would authorize the onset oftreatment before massive and irreversible lesions of the brain have occurred.Consequently, we designed a radio -clinical study using a multimodality MRIstandardized procedure that aimed to estimate differential sensitivity of FLAIR, DWI andMR spectroscopy for the diagnosis of human TSE. Here we report a case of familial fatalinsomnia with the D178N-129M mutation. FLAIR and diffusion-weighted sequenceswere normal in the whole brain notably in both thalami. However, spectroscopic studyshowed a striking increase of the peak of myo-inositol (mI) and of the mI/NAA ratio inthe thalamus when compared to the other studied brain regions of the patient (frontalisocortex, lenticular nucleus and cerebellar vermis) and to the thalami of control cases (n= 10). This metabolite pattern is indicating of gliosis. Because the MRI study wasperformed only two days before death, we were able to strictly correlate the spectroscopicdata with the neuropathological lesions (including the severity of astrogliosis andmicroglial activation) observed in the thalamus. From this observation, we can concludethat 1) MR spectroscopy can detect prion-related lesions even when other sequencesappear normal 2) spectroscopic metabolite pattern well correlates with theneuropathological one

Early diagnosis of human TSE by multimodality MRI: Spectroscopic detection of thalamic gliosis in a patient with FFI and normal FLAIR and diffusion-weighted imaging

International audienceRecently, several reports underlined the usefulness of brain MRI for the diagnosis ofCreutzfeldt-Jakob dis ease. FLAIR sequence and diffusion-weighted imaging (DWI) areconsidered as high sensitive sequences to detect signal alteration of the cortex and thedeep grey matter. Recent advances in therapeutic approach of patients with prion diseaseshave emphasized the need for earlier diagnostic markers that would authorize the onset oftreatment before massive and irreversible lesions of the brain have occurred.Consequently, we designed a radio -clinical study using a multimodality MRIstandardized procedure that aimed to estimate differential sensitivity of FLAIR, DWI andMR spectroscopy for the diagnosis of human TSE. Here we report a case of familial fatalinsomnia with the D178N-129M mutation. FLAIR and diffusion-weighted sequenceswere normal in the whole brain notably in both thalami. However, spectroscopic studyshowed a striking increase of the peak of myo-inositol (mI) and of the mI/NAA ratio inthe thalamus when compared to the other studied brain regions of the patient (frontalisocortex, lenticular nucleus and cerebellar vermis) and to the thalami of control cases (n= 10). This metabolite pattern is indicating of gliosis. Because the MRI study wasperformed only two days before death, we were able to strictly correlate the spectroscopicdata with the neuropathological lesions (including the severity of astrogliosis andmicroglial activation) observed in the thalamus. From this observation, we can concludethat 1) MR spectroscopy can detect prion-related lesions even when other sequencesappear normal 2) spectroscopic metabolite pattern well correlates with theneuropathological one

Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders

Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrPres), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders. © The Author 2012. Published by Oxford University Press