Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Linsenmeier, Luise; Mohammadi, Behnam; Shafiq, Mohsin; Frontzek, Karl; Bär, Julia; Shrivastava, Amulya Nidhi; Damme, Markus; Song, Feizhi; Schwarz, Alexander; Vela, Stefano Da; Massignan, Tania; Jung, Sebastian; Correia, Ângela; Schmitz, Matthias; Puig, Berta; Hornemann, Simone; Zerr, Inga; Tatzelt, Jörg; Biasini, Emiliano; Säftig, Paul; Schweizer, Michaela; Svergun, Dmitri I.; Amin, Ladan; Mazzola, Federica; Varani, Luca; Thapa, Simrika; Gilch, Sabine; Schätzl, Hermann; Triller, Antoine; Mikhaylova, Marina; Aguzzi, Adriano; Altmeppen, Hermann; Glatzel, Markus

doi:10.1126/sciadv.abj1826

Cited by 21 publications

(58 citation statements)

References 138 publications

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“…This results in a decreased level of the substrate for prion replication and a decreased level of the receptor for toxic oligomers [85,206]. Similar to fragment N1, shed PrP is also believed to be protective in prion diseases and other neurodegenerative diseases [40,79,81]. As mentioned in the previous section, recPrP is similar to shed PrP.…”

Section: Prion Protein and Neurodegenerationmentioning

confidence: 87%

“…The cleavage sheds PrP into the extracellular space, leaving a small number of amino acid residues on the cell surface. The cleavage was described in early research [35,39,76,77] but has received more attention in recent years due to the involvement of shed PrP in diseases [40,63,[78][79][80][81][82][83]. Similar to the α-cleavage, the shedding of PrP occurs in the presence of enzymes from the ADAM family.…”

Section: Shedding Of Prion Proteinmentioning

confidence: 99%

“…Due to the existence of more than one shed form, we hypothesized that the proteolytic site in the human sequence is not exclusively located between amino acid residues 228 and 229 but is located in the proximity of the C-terminus [95] (Figure 1). Recently, Linsenmeier et al published a comprehensive study on the mechanism stimulating PrP C proteolytic shedding [81]. Using animal models and controls, they showed that PrP shedding negatively correlates with prion conversion and that shed PrP is abundantly present in amyloid plaques.…”

Section: Shedding Of Prion Proteinmentioning

confidence: 99%

“…They also studied the influence of the binding of PrP-directed antibodies to PrP C in relation to shedding propensity. The binding of whole anti-PrP antibodies to the C-terminal structured domain of PrP C or single-chain antibody derivatives, directed towards repetitive epitopes within the octarepeat region of the N-terminal domain stimulated shedding, when the binding of whole anti-PrP antibodies to the octarepeat region of the N-terminal domain locked the N-terminal domain structure and evoked PrP C surface clustering, endocytosis and degradation in lysosomes [81].…”

Section: Shedding Of Prion Proteinmentioning

confidence: 99%

“…Neurodegeneration occurs in diseases such as prion disease, PD and AD due to the aggregation of PrP Sc [26,172,173], α-syn [174][175][176][177] and Aβ isoforms [178,179] and tau protein [180][181][182][183], respectively. Prion protein or prion protein fragments have been found to interact with aggregating agents in different neurodegenerative diseases but their roles depend on the studied conditions [24,81,184,185].…”

Section: Prion Protein and Neurodegenerationmentioning

confidence: 99%

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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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Section: Prion Protein and Neurodegenerationmentioning

confidence: 87%

Section: Shedding Of Prion Proteinmentioning

confidence: 99%

Section: Shedding Of Prion Proteinmentioning

confidence: 99%

Section: Shedding Of Prion Proteinmentioning

confidence: 99%

Section: Prion Protein and Neurodegenerationmentioning

confidence: 99%

See 3 more Smart Citations

Prion Protein: The Molecule of Many Forms and Faces

Kovač

Šerbec

2022

IJMS

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Gene Therapy Strategies for Prophylactic and Therapeutic Treatments of Human Prion Diseases

Camacho

Kong²

2023

Prions and 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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Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Abstract: Ligand-stimulated enzymatic release or cellular degradation of PrP may interfere with neurodegeneration-associated toxicity.

Cited by 21 publications

References 138 publications

Prion Protein: The Molecule of Many Forms and Faces

Prion Protein: The Molecule of Many Forms and Faces

Gene Therapy Strategies for Prophylactic and Therapeutic Treatments of Human Prion Diseases

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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