The role of host PrP in Transmissible Spongiform Encephalopathies

AbstractPrP has a central role in the Transmissible Spongiform Encephalopathies (TSEs), and mutations and polymorphisms in host PrP can profoundly alter the host's susceptibility to a TSE agent. However, precisely how host PrP influences the outcome of disease has not been established. To investigate this we have produced by gene targeting a series of inbred lines of transgenic mice expressing different PrP genes. This allows us to study directly the influence of the host PrP gene in TSEs. We have examined the role of glycosylation, point mutations, polymorphisms and PrP from different species on host susceptibility and the disease process both within the murine species and across species barriers

Loss of Octarepeats in Two Processed Prion Pseudogenes in the Red Squirrel, Sciurus vulgaris

The N-terminal region of the mammalian prion protein (PrP) contains an ‘octapeptide’ repeat which is involved in copper binding. This eight- or nine-residue peptide is repeated four to seven times, depending on the species, and polymorphisms in repeat number do occur. Alleles with three repeats are very rare in humans and goats, and deduced PrP sequences with two repeats have only been reported in two lemur species and in the red squirrel, Sciurus vulgaris. We here describe that the red squirrel two-repeat PrP sequence actually represents a retroposed pseudogene, and that an additional and older processed pseudogene with three repeats also occurs in this species as well as in ground squirrels. We argue that repeat numbers may tend to contract rather than expand in prion retropseudogenes, and that functional prion genes with two repeats may not be viable

Novel mutation of the PRNP gene of a clinical CJD case

BACKGROUND: Transmissible spongiform encephalopathies (TSEs), a group of neurodegenerative diseases, are thought to be caused by an abnormal isoform of a naturally occurring protein known as cellular prion protein, PrP(C). The abnormal form of prion protein, PrP(Sc )accumulates in the brain of affected individuals. Both isoforms are encoded by the same prion protein gene (PRNP), and the structural changes occur post-translationally. Certain mutations in the PRNP gene result in genetic TSEs or increased susceptibility to TSEs. CASE PRESENTATION: A 70 year old woman was admitted to the hospital with severe confusion and inability to walk. Relatives recognized memory loss, gait and behavioral disturbances over a six month period prior to hospitalization. Neurological examination revealed Creutzfeldt-Jakob disease (CJD) related symptoms such as incontinence, Babinski sign and myoclonus. EEG showed periodic sharp waves typical of sporadic CJD and cerebrospinal fluid analysis (CSF) was positive for the presence of the 14-3-3-protein. As the disease progressed the patient developed akinetic mutism and died in the tenth month after onset of the disease symptoms. Unfortunately, no autopsy material was available. PRNP sequencing showed the occurrence of a point mutation on one allele at codon 193, which is altered from ACC, coding for a threonine, to ATC, encoding an isoleucine (T193I). CONCLUSION: Here we report a novel mutation of the PRNP gene found in an elderly female patient resulting in heterozygosity for isoleucine and threonine at codon 193, in which normally homozygosity for threonine is expected (T193). The patient presented typical clinical symptoms of CJD. EEG findings and the presence of the 14-3-3 protein in the CSF, contributed to CJD diagnosis, allowing the classification of this case as a probable CJD according to the World Health Organization (WHO) accepted criteria

Australia's Oldest Marsupial Fossils and their Biogeographical Implications

Background: We describe new cranial and post-cranial marsupial fossils from the early Eocene Tingamarra Local Fauna in Australia and refer them to Djarthia murgonensis, which was previously known only from fragmentary dental remains. Methodology/Principal Findings: The new material indicates that Djarthia is a member of Australidelphia, a pan-Gondwanan clade comprising all extant Australian marsupials together with the South American microbiotheres. Djarthia is therefore the oldest known crown-group marsupial anywhere in the world that is represented by dental, cranial and postcranial remains, and the oldest known Australian marsupial by 30 million years. It is also the most plesiomorphic known australidelphian, and phylogenetic analyses place it outside all other Australian marsupials. Conclusions/Significance: As the most plesiomorphic and oldest unequivocal australidelphian, Djarthia may approximate the ancestral morphotype of the Australian marsupial radiation and suggests that the South American microbiotheres may be the result of back-dispersal from eastern Gondwana, which is the reverse of prevailing hypotheses

Some Histories of Molecular Evolution: Amniote Phylogeny, Vertebrate Eye Lens Evolution, and the Prion Gene

Contains fulltext : 60643.pdf (publisher's version ) (Open Access)In this thesis, the principles of molecular evolution and phylogeny are introduced in Chapter 1, while the subsequent chapters deal with the three topics mentioned in the title. Part I: Birds, reptiles and mammals are Amniota, organisms that have an amnion during their embryonal development. Even though these organisms have been studied for centuries, their interrelationships remain debated in some cases. In Chapter 2, the molecular phylogenetic position of the egg-laying mammals (Monotremata) is analysed, and Chapter 3 presents an example of rare genomic changes - in this case deletions in protein-coding DNA - that are very useful to distinguish relationships between the orders of placental mammals. Part II: The molecules that constitute the eye lens are stable, transparant proteins termed crystallins. In this part we report some typical examples of the origin and molecular evolution of the vertebrate eye lens crystallins. We present the (-crystallin genes from the platypus (Chapter 4) and the discovery in this species of a novel lens protein, upsilon-crystallin, which turns out to be overexpressed lactate dehydrogenase A (Chapter 5). We further present a paper on the evolution of regulatory sequences of the (B-crystallin gene, which are located in the bidirectional promoter between the head-to-head arranged (B-crystallin and HspB2 genes (Chapter 6). The (-crystallins originated evolutionarily from the family of small heat shock proteins. Some data about the evolution of this protein family in vertebrates and lower chordates are included in General Discussion and Summary (Chapter 8). Part III: Chapter 7 addresses the evolutionary aspects of the mammalian prion protein and touches on the evolution of the prion protein gene family. Specifically, the evolution of a repeat region in the vertebrate prion is discussed. The remarkable finding of a deviating prion gene in the squirrel is presented in General Discussion and Summary (Chapter 8).RU Radboud Universiteit Nijmegen, 18 mei 2004Promotor : Jong, W.W.W. de121 p

Molecular evolution of the mammalian prion protein

Prion protein (PrP) sequences are until now available for only six of the 18 orders of placental mammals. A broader comparison of mammalian prions might help to understand the enigmatic functional and pathogenic properties of this protein. We therefore determined PrP coding sequences in 26 mammalian species to include all placental orders and major subordinal groups. Glycosylation sites, cysteines forming a disulfide bridge, and a hydrophobic transmembrane region are perfectly conserved. Also, the sequences responsible for secondary structure elements, for N- and C-terminal processing of the precursor protein, and for attachment of the glycosyl-phosphatidylinositol membrane anchor are well conserved. The N-terminal region of PrP generally contains five or six repeats of the sequence P(Q/H)GGG(G/-)WGQ, but alleles with two, four, and seven repeats were observed in some species. This suggests, together with the pattern of amino acid replacements in these repeats, the regular occurrence of repeat expansion and contraction. Histidines implicated in copper ion binding and a proline involved in 4-hydroxylation are lacking in some species, which questions their importance for normal functioning of cellular PrP. The finding in certain species of two or seven repeats, and of amino acid substitutions that have been related to human prion diseases, challenges the relevance of such mutations for prion pathology. The gene tree deduced from the PrP sequences largely agrees with the species tree, indicating that no major deviations occurred in the evolution of the prion gene in different placental lineages. In one species, the anteater, a prion pseudogene was present in addition to the active gene

The platypus is in its place: nuclear genes and indels confirm the sister group on of monotremes and Therians

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Diurnal modulation of subthalamic beta oscillatory power in Parkinson’s disease patients during deep brain stimulation

Beta-band activity in the subthalamic local field potential (LFP) is correlated with Parkinson’s disease (PD) symptom severity and is the therapeutic target of deep brain stimulation (DBS). While beta fluctuations in PD patients are well characterized on shorter timescales, it is not known how beta activity evolves around the diurnal cycle, outside a clinical setting. Here, we obtained chronic recordings (34 ± 13 days) of subthalamic beta power in PD patients implanted with the Percept DBS device during high-frequency DBS and analysed their diurnal properties as well as sensitivity to artifacts. Time of day explained 41 ± 9% of the variance in beta power (p < 0.001 in all patients), with increased beta during the day and reduced beta at night. Certain movements affected LFP quality, which may have contributed to diurnal patterns in some patients. Future DBS algorithms may benefit from taking such diurnal and artifactual fluctuations in beta power into account

Mapping platypus SOX genes; autosomal location of SOX9 excludes it from sex determining role

In the absence of an SRY orthologue the platypus sex determining gene is unknown, so genes in the human testis determining pathway are of particular interest as candidates. SOX9 is an attractive choice because SOX9 deletions cause male-to-female sex reversal in humans and mice, and SOX9 duplications cause female-to-male sex reversal. We have localized platypus SOX9, as well as the related SOX10, to platypus chromosomes 15 and 10, respectively, the first assignments to these platypus chromosomes, and the first comparative mapping markers from human chromosomes 17 and 22. The autosomal localization of platypus SOX9 in this study contradicts the hypothesis that SOX9 acts as the sex determining switch in platypus.M.C. Wallis, M.L. Delbridge, A.J. Pask, A.E. Alsop, F. Grützner, P.C.M. O'Brien, W. Rens, M.A. Ferguson-Smith, J.A.M. Grave