Genetics. 2002 Aug;161(4):1425-35. A heritable structural alteration of the yeast mitochondrion.
Lockshon D.
Department of Genetics, University of Washington, Seattle, Washington 98195, USA. locksho.washington.edu
Prions have revived interest in hereditary change that is due to change in cellular structure. How pervasive is structural inheritance and what are its mechanisms? Described here is the initial characterization of [Leu(P)], a heritable structural change of the mitochondrion of Saccharomyces cerevisiae that often but not always accompanies the loss of all or part of the mitochondrial genome. Three phenotypes are reported in [Leu(P)] vs. [Leu(+)] strains: twofold slower growth, threefold slower growth in the absence of leucine, and a marked delocalization of nuclear-encoded protein destined for the mitochondrion. Introduction of mitochondria from a [Leu(+)] strain by cytoduction can convert a [Leu(P)] strain to [Leu(+)] and vice versa. Evidence against the Mendelian inheritance of the trait is presented. The incomplete dominance of [Leu(P)] and [Leu(+)] and the failure of HSP104 deletion to have any effect suggest that the trait is not specified by a prion but instead represents a new class of heritable structural change.
PMID:_12196390
J Neurosci. 2002 Sep 1;22(17):7471-7. Unhampered prion neuroinvasion despite impaired fast axonal transport in transgenic mice overexpressing four-repeat tau.
Kunzi V, Glatzel M, Nakano MY, Greber UF, Van Leuven F, Aguzzi A.
Institute of Neuropathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Transmissible spongiform encephalopathies often are caused by peripheral uptake of infectious prions, and the peripheral nervous system is involved in prion spread to the brain. Although the cellular prion protein is subjected to fast axonal transport, the mechanism of intranerval transport of infectious prions is unclear. Here we administered prions intranervally to transgenic mice overexpressing the four-repeat human tau protein, which exhibit defective fast axonal transport. These mice showed unaltered neuroinvasion, suggesting that transport mechanisms distinct from fast axonal transport effect prion neuroinvasion along peripheral nerves. Surprisingly, scrapie-sick tau transgenic mice accumulated intraneuronal deposits of hyperphosphorylated tau protein. The coincidence of tau and prion pathology resembled Gerstmann-Straussler-Scheinker syndrome. These findings identify tau pathology as a possible end stretch of prion-induced neurodegeneration.
PMID:_12196569
Acta Virol. 2002;46(1):31-9. Creutzfeldt-Jakob disease with E200K mutation in Slovakia: characterization and development.
Mitrova E, Belay G.
Institute of Preventive and Clinical Medicine, Bratislava, Slovak Republic. mitrovpkm.sk
Creutzfeldt-Jakob disease (CJD), the most important human prion disease, occurs in sporadic, iatrogenic and familial form. Except Slovakia and Israel, the recorded familial cases have never exceeded 10-15%. In the Slovak CJD group 95 out of 136 CJD cases (74.2%) carried a CJD-specific mutation in the prion protein gene (PRNP) at codon 200 (mutation E200K). All CJD(E200K) patients carried a heterozygous E200K mutation within the alelle with methionine at codon 129. No more than 53.7% were typical familial cases. The penetrance of the E200K mutation in 1975-2000 was 59.5%. The distribution of codon 129 polymorphism showed 78.6% of methionine-homozygous and 21.4% of methionine/valine-heterozygous patients. Genetic analysis performed on 278 CJD patient relatives demonstrated the E200K mutation in 97 (34.8%) of healthy relatives tested. The E200K mutation carriers were methionine-homozygous in 64% and methionine/valine-heterozygous in 36%. The relatives without the mutation showed a 54.9% methionine homozygosity, 10.4% valine homozygosity and 34.7% methionine/valine heterozygosity. Analysis ofthe E200K carriers provided evidence that the methionine homozygosity is a CJD risk factor, more efficient in CJD patients than in asymptomatic relatives. Th influence of both the E200K mutation and methionine homozygosity at codon 129 was evident in the duration of the clinical stage of CJD and in the immunoreactivity pattern of PrP resistant to proteases (PrP(res)). In the CJD(E200K) methionine-homozygous patients the mean duration ofthe disease was significantly shorter (3.7 +/- 2.0 months) than in the methionine/valine-heterozygous patients (7.84 +/- 7.3 months). Comparison of the PrP(res) positivity in the cerebellum of familial and sporadic CJD using specific polyclonal and monoclonal antibodies (MAbs) to PrP showed less conspicuous immune reaction in CJD(E200K) cases. Methionine-homozygous CJD patients were characteristic mainly by synaptic pattern of staining, while methionine/valine-heterozygous patients by PrP(res) granules and plaque-like structures. Most of numerous plaque-like PrP(res) deposits were found in sporadic valine/valine-homozygous cases. Potential professional risk was excluded in health facility workers. The percentage of professions related to farming was significantly higher in CJD(E200K) (48%) and sporadic CJD (44%) cases as compared to the employed population (9%).
Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. ariechicago.edu
A structuring and eventual exclusion of water surrounding backbone hydrogen bonds takes place during protein folding as hydrophobic residues cluster around such bonds. Taken as an average over all hydrogen bonds, the extent of desolvation is nearly a constant of motion, as revealed by re-examination of the longest all-atom trajectory with explicit solvent [Y. Duan & P. A. Kollman (1998) Science 282, 740]. Furthermore, this extent of desolvation is preserved across native soluble proteins, except for cellular prion proteins. Thus, a physico-chemical picture of prion-related disease emerges. The epitope for protein-X binding, the region undergoing vast conformational change and the trigger and locker for this change are inferred from the location of under-desolvated hydrogen bonds in the cellular prion protein.
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