ArticleThe Journal of cell biology2010
Signal sequence insufficiency contributes to neurodegeneration caused by transmembrane prion protein.
Article in The Journal of cell biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 82 citations in OpenAlex.
- Mechanisms of Quality Control in GPI-Anchored Proteins: The Central Role of the Lipid Anchor.International journal of molecular sciences · 2026Review
- Signal recognition particle-dependent secretome in humans.Scientific reports · 2026Article
- The degradation of extended protein isoforms points to a misfiring translation initiation process.Molecular genetics and genomics : MGG · 2025Article
- TMED9 coordinates the clearance of misfolded GPI-anchored proteins out of the ER and into the Golgi.PLoS biology · 2025Article
- TanGIBLE: A selective probe for evaluating hydrophobicity-exposed defective proteins in live cells.The Journal of cell biology · 2025Article
- The rapid degradation of translated upstream regions points to an inefficient translation initiation process.bioRxiv : the preprint server for biology · 2024Article
- Dipeptidyl peptidases and E3 ligases of N-degron pathways cooperate to regulate protein stability.The Journal of cell biology · 2024Article
- Pathogenic signal peptide variants in the human genome.NAR genomics and bioinformatics · 2023Article
- (Dys)functional insights into nucleic acids and RNA-binding proteins modulation of the prion protein and α-synuclein phase separation.Biophysical reviews · 2023Review
- New developments in prion disease research using genetically modified mouse models.Cell and tissue research · 2023Review
- The Endoplasmic Reticulum and the Fidelity of Nascent Protein Localization.Cold Spring Harbor perspectives in biology · 2023Review
- Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation.The Journal of biological chemistry · 2022Article
- ATP13A1 prevents ERAD of folding-competent mislocalized and misoriented proteins.Molecular cell · 2022Article
- The E3 Ubiquitin Ligase TRAF6 Interacts with the Cellular Prion Protein and Modulates Its Solubility and Recruitment to Cytoplasmic p62/SQSTM1-Positive Aggresome-Like Structures.Molecular neurobiology · 2022Article
- RETREG1/FAM134B mediated autophagosomal degradation of AMFR/GP78 and OPA1 -a dual organellar turnover mechanism.Autophagy · 2021Article
- Article
- The C-degron pathway eliminates mislocalized proteins and products of deubiquitinating enzymes.The EMBO journal · 2021Article
- Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.The Journal of clinical investigation · 2021Review
- Kinetically distinct processing pathways diversify the CD8Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Size-dependent secretory protein reflux into the cytosol in association with acute endoplasmic reticulum stress.Traffic (Copenhagen, Denmark) · 2020Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.