scholarly journals Protection from cytosolic prion protein toxicity by modulation of protein translocation

2004 ◽  
Vol 23 (23) ◽  
pp. 4550-4559 ◽  
Author(s):  
Neena S Rane ◽  
Jesse L Yonkovich ◽  
Ramanujan S Hegde
Keyword(s):  
Prion Protein ◽  
Protein Translocation ◽  
Protein Toxicity

scholarly journals Signal sequence insufficiency contributes to neurodegeneration caused by transmembrane prion protein

2010 ◽  
Vol 188 (4) ◽  
pp. 515-526 ◽  
Author(s):  
Neena S. Rane ◽  
Oishee Chakrabarti ◽  
Lionel Feigenbaum ◽  
Ramanujan S. Hegde
Keyword(s):  
Prion Protein ◽  
Protein Translocation ◽  
Signal Sequence ◽  
Signal Sequences ◽  
Hydrophobic Domain ◽  
Sequence Variations ◽  
Sufficient Magnitude ◽  
The Impact

Protein translocation into the endoplasmic reticulum is mediated by signal sequences that vary widely in primary structure. In vitro studies suggest that such signal sequence variations may correspond to subtly different functional properties. Whether comparable functional differences exist in vivo and are of sufficient magnitude to impact organism physiology is unknown. Here, we investigate this issue by analyzing in transgenic mice the impact of signal sequence efficiency for mammalian prion protein (PrP). We find that replacement of the average efficiency signal sequence of PrP with more efficient signals rescues mice from neurodegeneration caused by otherwise pathogenic PrP mutants in a downstream hydrophobic domain (HD). This effect is explained by the demonstration that efficient signal sequence function precludes generation of a cytosolically exposed, disease-causing transmembrane form of PrP mediated by the HD mutants. Thus, signal sequences are functionally nonequivalent in vivo, with intrinsic inefficiency of the native PrP signal being required for pathogenesis of a subset of disease-causing PrP mutations.

scholarly journals Prion Protein Translocation Mechanism Revealed by Pulling Force Studies

2020 ◽  
Vol 432 (16) ◽  
pp. 4447-4465 ◽  
Author(s):  
Theresa Kriegler ◽  
Sven Lang ◽  
Luigi Notari ◽  
Tara Hessa
Keyword(s):  
Prion Protein ◽  
Protein Translocation ◽  
Translocation Mechanism ◽  
Pulling Force

scholarly journals Cytosolic Prion Protein Toxicity Is Independent of Cellular Prion Protein Expression and Prion Propagation

2006 ◽  
Vol 81 (6) ◽  
pp. 2831-2837 ◽  
Author(s):  
Eric M. Norstrom ◽  
Mark F. Ciaccio ◽  
Benjamin Rassbach ◽  
Robert Wollmann ◽  
James A. Mastrianni
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Cultured Cells ◽  
Prion Diseases ◽  
Cerebellar Atrophy ◽  
Cellular Prion Protein ◽  
Cellular Toxicity ◽  
Prion Propagation ◽  
Gait Abnormalities ◽  
Protein Toxicity

ABSTRACT Prion diseases are transmissible neurodegenerative diseases caused by a conformational isoform of the prion protein (PrP), a host-encoded cell surface sialoglycoprotein. Recent evidence suggests a cytosolic fraction of PrP (cyPrP) functions either as an initiating factor or toxic element of prion disease. When expressed in cultured cells, cyPrP acquires properties of the infectious conformation of PrP (PrPSc), including insolubility, protease resistance, aggregation, and toxicity. Transgenic mice (2D1 and 1D4 lines) that coexpress cyPrP and PrPC exhibit focal cerebellar atrophy, scratching behavior, and gait abnormalities suggestive of prion disease, although they lack protease-resistant PrP. To determine if the coexpression of PrPC is necessary or inhibitory to the phenotype of these mice, we crossed Tg1D4(Prnp +/+ ) mice with PrP-ablated mice (TgPrnp o/o) to generate Tg1D4(Prnp o/o) mice and followed the development of disease and pathological phenotype. We found no difference in the onset of symptoms or the clinical or pathological phenotype of disease between Tg1D4(Prnp +/+ ) and Tg1D4(Prnp o/o) mice, suggesting that cyPrP and PrPC function independently in the disease state. Additionally, Tg1D4(Prnp o/o) mice were resistant to challenge with mouse-adapted scrapie (RML), suggesting cyPrP is inaccessible to PrPSc. We conclude that disease phenotype and cellular toxicity associated with the expression of cyPrP are independent of PrPC and the generation of typical prion disease.

scholarly journals An N-terminal Polybasic Domain and Cell Surface Localization Are Required for Mutant Prion Protein Toxicity

2011 ◽  
Vol 286 (16) ◽  
pp. 14724-14736 ◽  
Author(s):  
Isaac H. Solomon ◽  
Natasha Khatri ◽  
Emiliano Biasini ◽  
Tania Massignan ◽  
James E. Huettner ◽  
...  
Keyword(s):  
Cell Surface ◽  
Prion Protein ◽  
Surface Localization ◽  
Cell Surface Localization ◽  
Protein Toxicity

scholarly journals Ramanujan Hegde: The prion puzzle and protein translocation

2010 ◽  
Vol 191 (7) ◽  
pp. 1222-1223
Author(s):  
Caitlin Sedwick
Keyword(s):  
Prion Protein ◽  
Protein Translocation

Hegde uses prion protein as a model to explore how cells handle protein translocation and trafficking.

scholarly journals Supporting data on prion protein translocation mechanism revealed by pulling force studies

Data in Brief ◽  
2020 ◽  
Vol 31 ◽  
pp. 105931 ◽  
Author(s):  
Theresa Kriegler ◽  
Sven Lang ◽  
Luigi Notari ◽  
Tara Hessa
Keyword(s):  
Prion Protein ◽  
Protein Translocation ◽  
Translocation Mechanism ◽  
Pulling Force

Specific inhibition of hamster prion protein translocation by the dodecadepsipeptide valinomycin

2013 ◽  
Vol 319 (13) ◽  
pp. 2049-2057 ◽  
Author(s):  
Jiyeon Kim ◽  
Ilho Choi ◽  
Joong-Yeol Park ◽  
Sang-Wook Kang
Keyword(s):  
Prion Protein ◽  
Protein Translocation ◽  
Specific Inhibition

scholarly journals A Small-Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity

ChemMedChem ◽  
2017 ◽  
Vol 12 (16) ◽  
pp. 1286-1292 ◽  
Author(s):  
Tania Massignan ◽  
Valeria Sangiovanni ◽  
Silvia Biggi ◽  
Claudia Stincardini ◽  
Saioa R. Elezgarai ◽  
...  
Keyword(s):  
Prion Protein ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Protein Toxicity

scholarly journals A Nine Amino Acid Domain Is Essential for Mutant Prion Protein Toxicity

2011 ◽  
Vol 31 (39) ◽  
pp. 14005-14017 ◽  
Author(s):  
L. Westergard ◽  
J. A. Turnbaugh ◽  
D. A. Harris
Keyword(s):  
Amino Acid ◽  
Prion Protein ◽  
Acid Domain ◽  
Protein Toxicity ◽  
Amino Acid Domain

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

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