Taking advantage of physiological proteolytic processing of the prion protein for a therapeutic perspective in prion and Alzheimer diseases

Béland, Maxime; Roucou, Xavier

doi:10.4161/pri.27438

Cited by 11 publications

(10 citation statements)

References 64 publications

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“…It appears to be settled that the prion protein mediates mechanisms of neuroprotection (Martins et al, 2010 ; Biasini et al, 2012 ; Béland and Roucou, 2014 ). However, contributions of PrP C have been reported also in immune responses, energy metabolism, cancer, and stress conditions in general (Linden et al, 2008 ; Li et al, 2011 ; Mariante et al, 2012 ; Martin-Lannerée et al, 2014 ; Onodera et al, 2014 ; Bakkebø et al, 2015 ; Zeng et al, 2015 ).…”

Section: The Quest For the Function Of The Prion Proteinmentioning

confidence: 99%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

115

104

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The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.

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Section: The Quest For the Function Of The Prion Proteinmentioning

confidence: 99%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

115

104

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“…Second, binding of toxic oligomeric protein species, such as PrP Sc (in prion diseases [ 38 ]), Aβ (in Alzheimer’s disease [ 39 – 42 ]) or α-synuclein (in Parkinson’s disease [ 43 , 44 ]), to PrP C at the neuronal surface results in neurotoxic signaling. As for the physiological functions, increasing evidence suggests that proteolytic cleavages also impact on these pathogenic roles of the prion protein [ 28 , 45 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein

Linsenmeier

Mohammadi

Wetzel

et al. 2018

Mol Neurodegeneration

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BackgroundProteolytic processing of the prion protein (PrPC) by endogenous proteases generates bioactive membrane-bound and soluble fragments which may help to explain the pleiotropic roles of this protein in the nervous system and in brain diseases. Shedding of almost full-length PrPC into the extracellular space by the metalloprotease ADAM10 is of peculiar relevance since soluble PrP stimulates axonal outgrowth and is protective in neurodegenerative conditions such as Alzheimer’s and prion disease. However, molecular determinates and mechanisms regulating the shedding of PrP are entirely unknown.MethodsWe produced an antibody recognizing the neo-epitope of shed PrP generated by ADAM10 in biological samples and used it to study structural and mechanistic aspects affecting the shedding. For this, we investigated genetically modified cellular and murine models by biochemical and morphological approaches.ResultsWe show that the novel antibody specifically detects shed PrP in cell culture supernatants and murine brain. We demonstrate that ADAM10 is the exclusive sheddase of PrPC in the nervous system and reveal that the glycosylation state and type of membrane-anchorage of PrPC severely affect its shedding. Furthermore, we provide evidence that PrP shedding can be modulated by pharmacological inhibition and stimulation and present data suggesting that shedding is a relevant part of a compensatory network ensuring PrPC homeostasis of the cell.ConclusionsWith the new antibody, our study introduces a new tool to reliably investigate PrP-shedding. In addition, this study provides novel and important insight into the regulation of this cleavage event, which is likely to be relevant for diagnostic and therapeutic approaches even beyond neurodegeneration.

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“…We therefore decided to address this issue in vivo by generating transgenic mice overexpressing N1 and challenging them with prions. Such a mouse model has previously been predicted to be of "crucial importance" to assess the therapeutic potential of N1 in neurodegenerative conditions [75]. While our "protective" strategy eventually failed due to impaired secretion of transgenic N1, our study (i) provides the first proof of the recently described inefficient translocation of IDDs [6] in an animal model.…”

Section: Introductionmentioning

confidence: 63%

Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation

et al. 2020

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The structurally disordered N-terminal half of the prion protein (PrP C) is constitutively released into the extracellular space by an endogenous proteolytic cleavage event. Once liberated, this N1 fragment acts neuroprotective in ischemic conditions and interferes with toxic peptides associated with neurodegenerative diseases, such as amyloid-beta (Aβ) in Alzheimer's disease. Since analog protective effects of N1 in prion diseases, such as Creutzfeldt-Jakob disease, have not been studied, and given that the protease releasing N1 has not been identified to date, we have generated and characterized transgenic mice overexpressing N1 (TgN1). Upon intracerebral inoculation of TgN1 mice with prions, no protective effects were observed at the levels of survival, clinical course, neuropathological, or molecular assessment. Likewise, primary neurons of these mice did not show protection against Aβ toxicity. Our biochemical and morphological analyses revealed that this lack of protective effects is seemingly due to an impaired ER translocation of the disordered N1 resulting in its cytosolic retention with an uncleaved signal peptide. Thus, TgN1 mice represent the first animal model to prove the inefficient ER translocation of intrinsically disordered domains (IDD). In contrast to earlier studies, our data challenge roles of cytoplasmic N1 as a cell penetrating peptide or as a potent "anti-prion" agent. Lastly, our study highlights both the importance of structured domains in the nascent chain for proteins to be translocated and aspects to be considered when devising novel N1-based therapeutic approaches against neurodegenerative diseases.

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Taking advantage of physiological proteolytic processing of the prion protein for a therapeutic perspective in prion and Alzheimer diseases

Cited by 11 publications

References 64 publications

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein

Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation

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