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GPI Anchoring of Proteins in the ER Membrane01:29

GPI Anchoring of Proteins in the ER Membrane

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GPI-anchoring is a post-translational, reversible protein modification that is ubiquitous in eukaryotes. Such proteins are primarily present on the exoplasmic leaflet of the plasma membrane.
GPI-anchor structure
A sequence of 11 enzymatic reactions results in the synthesis of the complete GPI anchor consisting of a hydrophobic and a hydrophilic portion. The hydrophobic portion comprises phosphatidylinositol, while the hydrophilic part comprises polar groups like phosphoethanolamine,...
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Tail-anchoring of Proteins in the ER Membrane01:45

Tail-anchoring of Proteins in the ER Membrane

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Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
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The Anchoring-and-Adjustment Heuristic01:25

The Anchoring-and-Adjustment Heuristic

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In order to make good decisions, we use our knowledge and our reasoning. Often, this knowledge and reasoning is sound and solid. However, sometimes, we are swayed by biases or by others manipulating a situation. For example, let’s say you and three friends wanted to rent a house and had a combined target budget of $1,600. The realtor shows you only very run-down houses for $1,600 and then shows you a very nice house for $2,000. Might you ask each person to pay more in rent to get the...
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Anchoring Junctions01:03

Anchoring Junctions

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Anchoring junctions are multiprotein complexes that help cells connect to other cells and the extracellular matrix. Anchoring junctions are present on the lateral and basal surfaces of cells, providing strong and flexible connections. Focal adhesions are often formed due to cell interactions with the ECM substrata, which initiate signal transduction via kinase cascades and other mechanisms. Together, they provide stability and tissue integrity. There are three types of anchoring junctions:...
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Lipids as Anchors01:32

Lipids as Anchors

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In the plasma membrane, the lipids forming the bilayer can also act as an anchor to tether proteins to the membrane. The three main types of lipid anchors found in eukaryotes are – prenyl groups, fatty acyl groups, and glycosylphosphatidylinositol or GPI groups. Prenyl and fatty acyl groups act as anchors on the cytosolic surface of the membrane, whereas GPI anchors proteins on the extracellular side.
The carboxy-terminal of most of the prenylated proteins, such as Ras proteins, contains...
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Introduction to Membrane Proteins01:16

Introduction to Membrane Proteins

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The cell membrane, or plasma membrane, is an ever-changing landscape. It is described as a fluid mosaic where various macromolecules are embedded in the phospholipid bilayer. Among the macromolecules are proteins. The protein content varies across cell types. For example, mitochondrial inner membranes contain ~76% protein content, while myelin contains ~18% protein content. Individual cells contain many types of membrane proteins—red blood cells contain over 50—and different cell...
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Articles linked to this work by shared authors, journal, and citation graph.

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Leveraging the dominant-negative effect of the kuru-protective G127V prion protein variant as a novel therapeutic strategy.

Neurobiology of disease·2026
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Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs.

PLoS pathogens·2026
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Leveraging the dominant-negative effect of the kuru-protective G127V prion protein variant as a novel therapeutic strategy.

bioRxiv : the preprint server for biology·2026
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Related Experiment Video

Updated: Jan 30, 2026

Prion Safety Laboratory Swipe Test
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Prion Safety Laboratory Swipe Test

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Membrane-anchored PrPSc is the trigger for prion synaptotoxicity.

Jean R P Gatdula1, Robert C C Mercer1, Jose Andres Alepuz Guillen1

  • 1Department of Biochemistry and Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States of America.

Plos Pathogens
|January 28, 2026
PubMed
Summary
This summary is machine-generated.

Prion diseases involve toxic protein (PrPSc) signaling that damages synapses. This study found that newly formed PrPSc on neuronal surfaces triggers this damage, suggesting G126V PrP mutations may offer a therapeutic strategy against prion diseases.

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Detection of Abnormal Prion Protein by Immunohistochemistry
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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Prion diseases are characterized by neuropathological damage caused by prions (PrPSc).
  • A known synaptotoxic pathway involves extracellular PrPSc stimulating NMDA receptors, leading to synaptic dysfunction.
  • It remains unclear if this pathway is directly linked to PrPC-to-PrPSc conversion or can be initiated independently.

Purpose of the Study:

  • To investigate whether synaptotoxic signaling in prion diseases requires de novo PrPSc formation at the neuronal surface.
  • To determine if extracellular PrPSc can initiate synaptotoxicity independently of PrPC conversion.
  • To explore the therapeutic potential of mutations that inhibit PrPC-PrPSc conversion.

Main Methods:

  • Utilized neuronal expression of PrPC mutants (G126V, V208M) resistant to conversion.
  • Applied heterologous PrPSc to neurons expressing homologous PrPC to block conversion.
  • Assessed synaptotoxicity by quantifying dendritic spine density in primary hippocampal neurons after prion exposure.

Main Results:

  • PrPC mutants G126V and V208M significantly impaired or blocked PrPC-PrPSc conversion.
  • Expression of G126V PrP completely prevented spine retraction across multiple prion strains.
  • Inter-species PrPC expression attenuated spine retraction, indicating a requirement for homologous conversion.

Conclusions:

  • Newly formed PrPSc at the neuronal surface is essential for initiating prion-mediated synaptotoxic signaling.
  • Synaptotoxicity does not appear to be initiated by extracellular PrPSc independently of conversion.
  • The G126V PrP mutation shows promise as a therapeutic strategy to inhibit PrPSc conversion in prion diseases.