A transmembrane form of the prion protein in neurodegenerative disease.

  title={A transmembrane form of the prion protein in neurodegenerative disease.},
  author={Ramanujan S. Hegde and James A. Mastrianni and Michael R. Scott and Kathryn A. Defea and Patrick J. Tremblay and Marilyn Torchia and Stephen J. DeArmond and Stanley B. Prusiner and Vishwanath R. Lingappa},
  volume={279 5352},
At the endoplasmic reticulum membrane, the prion protein (PrP) can be synthesized in several topological forms. The role of these different forms was explored with transgenic mice expressing PrP mutations that alter the relative ratios of the topological forms. Expression of a particular transmembrane form (termed CtmPrP) produced neurodegenerative changes in mice similar to those of some genetic prion diseases. Brains from these mice contained CtmPrP but not PrPSc, the PrP isoform responsible… 

Neurodegenerative Illness in Transgenic Mice Expressing a Transmembrane Form of the Prion Protein

CtmPrP in neurons cultured from transgenic mice is localized to the Golgi apparatus, rather than to the endoplasmic reticulum as in transfected cell lines, and development of the neurodegenerative phenotype is strongly dependent on coexpression of endogenous, wild-type PrP.

Targeting of the prion protein to the cytosol: mechanisms and consequences.

A complex regulation of the biogenesis of PrP is revealed, which provides interesting new insight into toxic activities of pathogenic protein conformers and quality control pathways of ER-targeted proteins.

The consequences of pathogenic mutations to the human prion protein.

The current evidence for such effects of single point mutations is discussed, indicating that PrP can be affected in many different ways, although questions remain about the mechanism by which mutations cause disease.

Trafficking of the cellular isoform of the prion protein.

THREE Cell Biology of Prion Protein

The latest findings on the fundamental aspects of prions biology are reviewed, from the PrP biosynthesis, function, and structure up to its intracellular traffic and analyze the possible roles of the different topological isoforms of the protein, as well as the GPI anchor, in the pathogenesis of the disease.

Conformational conversion of prion protein in prion diseases.

Understanding the mechanism of conformational conversion of prion protein is essential for the biomedical research and the treatment of prions, and the characterization of cofactors interacting with prionprotein might provide new diagnostic and therapeutic strategies.

Prion Protein Biogenesis: Implications for Neurodegeneration

The studies lead to the hypothesis that CtmPrP is a transducer of signals for apoptotic neuronal cell death, and it is suggested that PrP is just one of a family of complex proteins that are regulated at the level of co-translational translocation, whose dysregulation results in disease.

Cell Biology of Prion Protein.

A transmembrane form of the prion protein contains an uncleaved signal peptide and is retained in the endoplasmic Reticulum.

It is shown that a mutant form of PrP that is synthesized exclusively with the (Ctm)PrP topology is retained in the endoplasmic reticulum and is degraded by the proteasome, and it is demonstrated that the mutant contains an uncleaved, N-terminal signal peptide as well as a C-Terminal glycolipid anchor.

Mechanism of aggregation and membrane interactions of mammalian prion protein.




Prion diseases of humans and animals

Investigation of prion diseases may give insights into the more common neurodegenerative diseases and argue that a factor(s) designated protein X functions in the formation of PrPSc, perhaps as a molecular chaperone.

Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity

The results presented indicate that the conformation of PrP sc functions as a template in directing the formation of nascent PrPSc and suggest a mechanism to explain strains of prions where diversity is encrypted in the conformed PrP Sc.

Heritable disorder resembling neuronal storage disease in mice expressing prion protein with deletion of an α-helix

Mice constructed carrying prion protein transgenes with individual regions of putative secondary structure deleted remained healthy at >400 days of age, whereas those with either of carboxy-terminal α-helices deleted spontaneously developed fatal CNS illnesses similar to neuronal storage diseases.

NMR structure of the mouse prion protein domain PrP(121–231)

The nuclear magnetic resonance (NMR) structure of the autonomously folding PrP domain contains most of the point-mutation sites that have been linked, in human PrP, to the occurrence of familial prion diseases, and shows that these mutations occur within, or directly adjacent to, regular secondary structures.

Spontaneous neurodegeneration in transgenic mice with mutant prion protein

Many of the clinical and pathological features of Gerstmann-Straussler-Scheinker syndrome are reproduced in transgenic mice containing a prion protein with a single amino acid substitution, illustrating that a neurodegenerative process similar to a human disease can be genetically modeled in animals.

Evidence for a secretory form of the cellular prion protein.

It is reported that PrP can also exist as a secreted protein, and both the membrane and secretory forms of PrP appear to be generated from the same pool of nascent chains.

Cell-free formation of protease-resistant prion protein

The conversion of PrPc to protease-resistant forms similar to PrPSc in a cell-free system composed of substantially purified constituents is reported, providing direct evidence that PrP sc derives from specific PrP c–PrPSc interactions.

Determinants of carboxyl-terminal domain translocation during prion protein biogenesis.

A model in which a metastable "trans Membrane" intermediate, residing within the aqueous environment of the translocation channel, can be converted into either the integrated transmembrane or the fully translocated form of PrP, perhaps directed by trans-acting factor (s).

Inherited Prion Diseases and Transmission to Rodents

Prion diseases have a wide range from infectious disease to non‐infectious, hereditary metabolic disease and Polymorphism at codon 129 may modify the phenotypes and transmission rate to mice.

Unusual topogenic sequence directs prion protein biogenesis.

System-dependent topology conferred by addition of RRL to WG translation products suggests that this sequence interacts with one or more cytosolic factors.