Regional distribution of anchorless prion protein, PrP226*, in the human brain

Lukan, Anja; Černilec, Maja; Vranac, Tanja; Popović, Mara; Šerbec, Vladka Čurin

doi:10.4161/pri.28388

Cited by 8 publications

(12 citation statements)

References 23 publications

(32 reference statements)

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“…27 In addition to PrP-infected samples, we have shown that PrP226* is also present in the healthy brain, albeit in small amounts. 27,29 We are not the only research group to describe this PrP form. As indicated above, PrP226* was concurrently described by Jansen and coworkers.…”

Section: V5b2 and Prp226*mentioning

confidence: 67%

“…Analysis of aggregates in patients with sporadic Creutzfeldt-Jakob disease (sCJD) 27,28 and Gerstmann-Straussler-Scheinker (GSS) syndrome [29][30][31][32] has shown that apart from PrP Sc , aggregates are built from anchorless PrP and other variants of PrP without the GPI anchor. Initially, the conversion from PrP C to PrP Sc was thought to occur only when PrP C was bound to the cell membrane by the GPI anchor, but a study by Chesebro and coworkers showed the opposite.…”

Section: Prps That Lack the Gpi Anchor Anchorless Prpmentioning

confidence: 99%

“…To undoubtedly determine the presence of PrP226* in the PrP Sc aggregates using this monoclonal antibody, we denatured the sample before the analysis to release all V5B2 epitopes from the aggregates. 27,29 Our monoclonal antibody also enables a sensitive determination of PrP226* in the brains of TSE patients using dissociation-enhanced lanthanide fluorescence immunoassay 29 and enzyme-linked immunosorbent assay. 27 In addition to PrP-infected samples, we have shown that PrP226* is also present in the healthy brain, albeit in small amounts.…”

Section: V5b2 and Prp226*mentioning

confidence: 99%

“…27,29 Our monoclonal antibody also enables a sensitive determination of PrP226* in the brains of TSE patients using dissociation-enhanced lanthanide fluorescence immunoassay 29 and enzyme-linked immunosorbent assay. 27 In addition to PrP-infected samples, we have shown that PrP226* is also present in the healthy brain, albeit in small amounts. 27,29 We are not the only research group to describe this PrP form.…”

Section: Prps That Lack the Gpi Anchormentioning

confidence: 99%

See 3 more Smart Citations

Prion Proteins Without the Glycophosphatidylinositol Anchor: Potential Biomarkers in Neurodegenerative Diseases

Kovač

Šerbec

2018

Biomark�Insights

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Prion protein (PrP) is a biomolecule that is involved in neuronal signaling, myelinization, and the development of neurodegenerative diseases. In the cell, PrP is shed by the ADAM10 protease. This process generates PrP molecules that lack glycophosphatidylinositol anchor, and these molecules incorporate into toxic aggregates and neutralize toxic oligomers. Due to this dual role, these molecules are important biomarkers for neurodegenerative diseases. In this review, we present shed PrP as a potential biomarker, with a focus on PrP226*, which may be the main biomarker for predicting neurodegenerative diseases in humans.

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Section: V5b2 and Prp226*mentioning

confidence: 67%

Section: Prps That Lack the Gpi Anchor Anchorless Prpmentioning

confidence: 99%

Section: V5b2 and Prp226*mentioning

confidence: 99%

Section: Prps That Lack the Gpi Anchormentioning

confidence: 99%

See 2 more Smart Citations

Prion Proteins Without the Glycophosphatidylinositol Anchor: Potential Biomarkers in Neurodegenerative Diseases

Kovač

Šerbec

2018

Biomark�Insights

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“…The authors characterized two patients with prion disease who carried stop mutations at positions Y226X and Q227X and expressed the respective forms. Using a monoclonal antibody V5B2 [89] that specifically binds to a fragment of PrP ending with Tyr226, we concurrently described the existence of a free form of PrP named PrP226* [90][91][92][93][94]. The distribution of PrP226* in the human brain has been associated with the distribution of PrP Sc [90,94].…”

Section: Shedding Of Prion Proteinmentioning

confidence: 99%

Prion Protein: The Molecule of Many Forms and Faces

Kovač

Šerbec

2022

IJMS

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Cellular prion protein (PrPC) is a glycosylphosphatidylinositol (GPI)-anchored protein most abundantly found in the outer membrane of neurons. Due to structural characteristics (a flexible tail and structured core), PrPC interacts with a wide range of partners. Although PrPC has been proposed to be involved in many physiological functions, only peripheral nerve myelination homeostasis has been confirmed as a bona fide function thus far. PrPC misfolding causes prion diseases and PrPC has been shown to mediate β-rich oligomer-induced neurotoxicity in Alzheimer’s and Parkinson’s disease as well as neuroprotection in ischemia. Upon proteolytic cleavage, PrPC is transformed into released and attached forms of PrP that can, depending on the contained structural characteristics of PrPC, display protective or toxic properties. In this review, we will outline prion protein and prion protein fragment properties as well as overview their involvement with interacting partners and signal pathways in myelination, neuroprotection and neurodegenerative diseases.

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Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases

Song,

Kovac,

Mohammadi

et al. 2024

Acta Neuropathol

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Proteolytic cell surface release (‘shedding’) of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.

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Regional distribution of anchorless prion protein, PrP226*, in the human brain

Cited by 8 publications

References 23 publications

Prion Proteins Without the Glycophosphatidylinositol Anchor: Potential Biomarkers in Neurodegenerative Diseases

Prion Proteins Without the Glycophosphatidylinositol Anchor: Potential Biomarkers in Neurodegenerative Diseases

Prion Protein: The Molecule of Many Forms and Faces

Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases

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