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. 2012;1(1):15-31.
Epub 2012 May 15.

Proteolytic processing of the prion protein in health and disease

Hermann C Altmeppen  1 , Berta Puig, Frank Dohler, Dana K Thurm, Clemens Falker, Susanne Krasemann, Markus Glatzel
Affiliations

Proteolytic processing of the prion protein in health and disease

Hermann C Altmeppen et al. Am J Neurodegener Dis. 2012.

Abstract

A variety of physiological functions, not only restricted to the nervous system, are discussed for the cellular prion protein (PrP(C)). A prominent, non-physiological property of PrPC is the conversion into its pathogenic isoform (PrP(Sc)) during fatal, transmissible, and neurodegenerative prion diseases. The prion protein is subject to posttranslational proteolytic processing and these cleavage events have been shown i) to regulate its physiological functions, ii) to produce biologically active fragments, and iii) to potentially influence the course of prion disease. Here, we give an overview on the proteolytic processing under physiological and pathological conditions and critically review what is currently known about the three main cleavage events of the prion protein, namely α-cleavage, β-cleavage, and ectodomain shedding. The biological relevance of resulting fragments as well as controversies regarding candidate proteases, with special emphasis on members of the A-disintegrin-and-metalloproteinase (ADAM) family, will be discussed. In addition, we make suggestions aimed at facilitating clarity and progress in this important research field. The better understanding of this issue will not only answer basic questions in prion biology but will likely impact research on other neurodegenerative diseases as well.

Keywords: ADAM10; ADAM17; Prion protein; ectodomain shedding; proteolytic processing; α-cleavage; β-cleavage.

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Figures

Figure 1
Figure 1
Schematic representation of the prion protein. (A) The prion protein is located in lipid rafts and attached to the outer leaflet of the cellular membrane via a GPI-anchor. The flexible N-terminal part of the protein - among other features - harbors a neurotoxic domain (red box) and is able to bind copper ions and oligomeric amyloid β (purple triangles). The C-terminal part of PrPC has a globular structure and comprises up to two N-glycan side chains. Involvement of PrPC in protective or toxic signalling (dotted thunderbolt) requires accessory molecules (not shown) to bypass the lipid bilayer. (B) Linear representation of the primary sequence of murine PrPC showing important protein domains. After removal of the N-terminal signal sequence (aa 1-22; grey box) by signal peptidases in the ER and the C-terminal signal sequence for the attachment of the GPI-anchor (aa 231-254; grey box), the mature prion protein comprises an octameric repeat region (aa 51-90; dark green), a neurotoxic domain (aa 105-125; red box), a hydrophobic core (aa 111-134; dotted box), a disulfide bridge (between aa 178 and 213), and two variably occupied N-glycosylation sites (aa 180 and 196). The three most important cleavage events are indicated by arrows. (I) α-cleavage gives rise to a soluble N1 fragment of 11 kDa and a membrane-bound C1 fragment of 18 kDa. Of note, this cleavage destroys the neurotoxic domain. (II) β-cleavage at the end of the octameric repeat region produces N2 (9 kDa) and C2 (20 kDa) fragments. (III) Ectodomain shedding close to the GPI-anchor results in the release of nearly full-length PrP from the membrane. References are given in the text.
Figure 2
Figure 2
Model of the α-cleavage of PrPC. The α-PrPase produces membrane-attached C1 and soluble N1 fragments. C1 plays a dual role by initiating apoptotic signalling (a) and its involvement in trophic signalling onto Schwann cells to maintain the myelin sheath (b). Due to the loss of the neurotoxic domain, C1 is unable to misfold into the pathogenic isoform PrPSc and, in addition, might be a dominant negative inhibitor of the conversion process (c). The released N1 fragment is involved in neuroprotective signalling (d). While β-sheet-rich oligomers are thought to bind to the N-terminus of PrPC to induce toxic signalling, α-cleavage not only prevents this interaction but produces N1 that might bind these oligomers and block their toxicity (e). References are given in the text.
Figure 3
Figure 3
Lack of ADAM10 results in elevated amounts of PrPC and loss of PrP shedding. (A) Increased immunoreactivity for PrPC (mouse monoclonal antibody POM1 was used) in brains of embryonic mice with an ADAM10 knockout in neural precursor cells (III and IV) compared to littermate controls (I and II). II and IV represent magnifications of cortex area (see boxes in I and III respectively). Scale bar is 50 μm. (B) Immunoprecipitation (IP) of released PrP fragments in media supernatants of primary neurons derived from embryonic PrPC knockout (Prnp0/0), wildtype (wt), and PrPC-overexpressing (tga20) mice as well as from ADAM10 conditional knockout (ADAM10 cKO) and littermate controls reveals a loss of shedding when ADAM10 is lacking while production of the N1 fragment is not affected (d, m, u = di-, mono-, unglycosylated forms of PrPC; IgG-LC = light chain of capture antibody POM2). (B) is taken from [41] originally published by BioMed Central.
Figure 4
Figure 4
Ectodomain shedding and the role of anchorless PrP. ADAM10-mediated shedding releases nearly full-length PrP (and C1 fragments) from the plasma membrane (a) thereby impairing toxic and protective signaling via PrPC. By reducing the substrate for prion conversion, shedding might have an protective role in prion disease (b). On the other hand, shed PrP was shown to be convertible to PrPSc (c) and shedding might release PrPSc molecules from the membrane (d). Anchorless PrPSc might facilitate the spread of infectivity and induce neurotoxicity and misfolding of PrPC in other cells (e). References are given in the text. It might be speculated that shed PrP acts as a trophic factor and is involved in neuroprotective signalling (f). In addition and as shown for the N1 fragment, shed PrP might likewise be able to bind β-sheet-rich oligomers thereby blocking their toxic effects (g) and potentially guiding them towards phagocytosis and degradation (h).
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References

    1. Riek R, Hornemann S, Wider G, Glockshuber R, Wüthrich K. NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231) FEBS Lett. 1997;413:282–288. - PubMed
    1. Biasini E, Turnbaugh JA, Unterberger U, Harris DA. Prion protein at the crossroads of physiology and disease. Trends Neurosci. 2012;35:92–103. - PMC - PubMed
    1. Brugger B, Graham C, Leibrecht I, Mombelli E, Jen A, Wieland F, Morris R. The membrane domains occupied by glycosylphosphatidylinositol-anchored prion protein and Thy-1 differ in lipid composition. J Biol Chem. 2004;279:7530–7536. - PubMed
    1. Taylor DR, Hooper NM. The prion protein and lipid rafts. Mol Membr Biol. 2006;23:89–99. - PubMed
    1. Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR. Physiology of the prion protein. Physiol Rev. 2008;88:673–728. - PubMed

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