FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2077887509> ?p ?o ?g. }

• W2077887509 endingPage "996" @default.
• W2077887509 startingPage "994" @default.
• W2077887509 abstract "Inactivation of mahogunin, an E3 ubiquitin ligase, causes a spongiform encephalopathy resembling prion disease. Chakrabarti and Hegde, 2009Chakrabarti S. Hegde R.S. Cell. 2009; (this issue)PubMed Google Scholar now report that prion proteins with aberrant topologies inactivate mahogunin, providing a plausible explanation for certain aspects of prion pathology. Inactivation of mahogunin, an E3 ubiquitin ligase, causes a spongiform encephalopathy resembling prion disease. Chakrabarti and Hegde, 2009Chakrabarti S. Hegde R.S. Cell. 2009; (this issue)PubMed Google Scholar now report that prion proteins with aberrant topologies inactivate mahogunin, providing a plausible explanation for certain aspects of prion pathology. Transmissible spongiform encephalopathies, or prion diseases, are neurodegenerative conditions caused by prions, atypical infectious agents consisting of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC). PrPC is a cell-surface GPI-anchored glycoprotein that is normally produced in abundance in brain, muscle, and the immune system (Aguzzi et al., 2008Aguzzi A. Sigurdson C. Heikenwaelder M. Annu. Rev. Pathol. 2008; 3: 11-40Crossref PubMed Scopus (284) Google Scholar). Although we have a robust model of how prions replicate, we still do not understand how and why the central nervous system (CNS) is preferentially damaged. The relatively small amounts of PrPSc needed to disrupt CNS function suggest that prions target highly specific weak points in the system. The key features of nearly all prion diseases are transmissibility and a foamy pattern (spongiosis) of brain tissue that is visible on histological sections. Spongiosis is due primarily to intraneuronal vacuoles containing membrane fragments and, sometimes, degenerating organelles, but the etiology of this highly characteristic pathology is unclear. Much excitement surrounded the discovery that mutations in an E3 ubiquitin ligase called mahogunin cause similar spongiform changes in the CNS of “mahoganoid” mice (He et al., 2003He L. Lu X.Y. Jolly A.F. Eldridge A.G. Watson S.J. Jackson P.K. Barsh G.S. Gunn T.M. Science. 2003; 299: 710-712Crossref PubMed Scopus (119) Google Scholar). This supported the notion that disorders of the proteasome degradation pathway may be involved in the toxicity of PrPSc. However, recombinant prion protein does not undergo ubiquitination by mahogunin, and the potential link between mahogunin and the pathogenic prion protein has remained untested. In this issue, Chakrabarti and Hegde, 2009Chakrabarti S. Hegde R.S. Cell. 2009; (this issue)PubMed Google Scholar report a physical interaction between mahogunin and PrPC that has acquired improper topologies. Although the bulk of PrPC is turned over via the endolysosomal system, some is degraded by the proteasome (Ma et al., 2002Ma J. Wollmann R. Lindquist S. Science. 2002; 298: 1781-1785Crossref PubMed Scopus (429) Google Scholar and references therein), which is the main degradation system for cytosolic proteins (Figure 1). A minor pathogenic form of PrP called cyPrP, which lacks a secretory signal peptide and is constitutively released into the cytosol, is extremely neurotoxic to cerebellar neurons of transgenic mice (Ma et al., 2002Ma J. Wollmann R. Lindquist S. Science. 2002; 298: 1781-1785Crossref PubMed Scopus (429) Google Scholar). The neurotoxicity of cyPrP may be more widespread than initially appreciated as transgenic mice with inducible forebrain-restricted expression of cyPrP show behavioral and neuropathological phenotypes (Wang et al., 2009Wang X. Bowers S.L. Wang F. Pu X.A. Nelson R.J. Ma J. Biochim. Biophys. Acta. 2009; (Published online March 10, 2009)https://doi.org/10.1016/j.bbadis.2009.02.014Crossref Scopus (30) Google Scholar). In previous work, Hegde and colleagues noted that cyPrP accumulates in the cytosol due to its inefficient import into the endoplasmic reticulum (ER) attributable to a weak secretory signal sequence. Indeed, transgenic mice expressing PrP with a very inefficient secretory signal exhibit a mild neurodegenerative phenotype (Rane et al., 2008Rane N.S. Kang S.W. Chakrabarti O. Feigenbaum L. Hegde R.S. Dev. Cell. 2008; 15: 359-370Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), supporting the view that the cytosolic accumulation of PrPC can be neurotoxic. However, there has been much debate as to whether the cytosolic accumulation pathway is relevant to the toxicity of naturally occurring prion infections. To some extent, this discussion reflects the fact that it is extremely difficult to detect cyPrP and hence to design an experiment that would disprove its relevance to prion diseases. In their new work, Chakrabarti and Hegde, 2009Chakrabarti S. Hegde R.S. Cell. 2009; (this issue)PubMed Google Scholar discover a functional interaction between cyPrP and mahogunin, leading to an exciting new model for how mislocalized prion proteins can lead to neuronal damage and loss. Given that naked cyPrP is unstable unless the proteasome is inhibited pharmacologically, the authors began by developing a GFP-tagged version of cyPrP that has greatly enhanced stability. Coexpression of tagged mahogunin led to a tight association with aggregated cyPrP. Mahogunin did not aggregate with a fragment of huntingtin, a protein involved in a different type of neurodegenerative disease, suggesting that mahogunin does not bind generically to all pathogenic protein aggregates. Another putative neurotoxic PrP species, CtmPrP, displays an atypical transmembrane topology and is also associated with mahogunin. Lysosomal morphology was altered in the same way by loss of mahogunin and by cyPrP, suggesting a connection between these two proteins. As no substrates of mahogunin are known, the authors relied on lysosomal morphology as a surrogate of mahogunin function. Finally, the authors observed loss of mahogunin immunoreactivity and altered lysosomal morphology in the brains of mice expressing a mutant form of PrP that favors production of CtmPrP. The finding of “bilaminar” spongiosis (a pattern of vacuolation that affects two discontinuous cortical layers) in human brain specimens rings alarm bells with any neuropathologist, as it is a harbinger of the prototypic prion disease of humans, Creutzfeldt-Jakob disease. The new study is tantalizing as it suggests that in order to decipher the molecular basis of prion toxicity we may need to enumerate and functionally assess the substrates of mahogunin. However, it will be crucial to assess whether mahogunin plays a role in mediating neurodegeneration in naturally occurring prion diseases such as Creutzfeldt-Jakob disease and in experimental models of prion infection such as transmission to mice of Rocky Mountain Laboratory (RML) scrapie prions. Although it was the spongiosis in mahoganoid mice that flagged the prion-mahogunin connection, the spongiosis phenotype raises some tough questions. Given that mahoganoid mice develop spongiosis and that both cyPrP and CtmPrP appear to sequester mahogunin, it would be gratifying to observe spongiosis in mice overproducing cyPrP and CtmPrP. However, although neither mouse strain is healthy, spongiform changes in brain tissue are not prominent (Ma et al., 2002Ma J. Wollmann R. Lindquist S. Science. 2002; 298: 1781-1785Crossref PubMed Scopus (429) Google Scholar, Rane et al., 2008Rane N.S. Kang S.W. Chakrabarti O. Feigenbaum L. Hegde R.S. Dev. Cell. 2008; 15: 359-370Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, Stewart and Harris, 2005Stewart R.S. Harris D.A. J. Biol. Chem. 2005; 280: 15855-15864Crossref PubMed Scopus (45) Google Scholar). Conversely, spongiosis is a hallmark of prion infections, yet the extent to which typical prion infections lead to the generation of cyPrP or CtmPrP is unclear, and the effect of prion infections on the cellular bioavailability of mahogunin has not been investigated. So might spongiosis be a “red-herring” phenotypic similarity in mahogunin-deficient and prion-infected mice? Investigating this issue will be important given that PrP oligomers can interfere directly with the proteolytic activity of the proteasome (Kristiansen et al., 2007Kristiansen M. Deriziotis P. Dimcheff D.E. Jackson G.S. Ovaa H. Naumann H. Clarke A.R. van Leeuwen F.W. Menendez-Benito V. Dantuma N.P. et al.Mol. Cell. 2007; 26: 175-188Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar), suggesting that there are mahogunin-independent pathways of PrPSc toxicity. Also, cyPrP interacts with the hydrophobic core of membranes implying that it could subvert the function of synaptic vesicles (Wang et al., 2006Wang X. Wang F. Arterburn L. Wollmann R. Ma J. J. Biol. Chem. 2006; 281: 13559-13565Crossref PubMed Scopus (55) Google Scholar). Another poorly understood aspect of prion toxicity is the role of PrPC in cellular damage. We know that PrPC is generally required for PrPSc to become neurotoxic (Brandner et al., 1996Brandner S. Isenmann S. Raeber A. Fischer M. Sailer A. Kobayashi Y. Marino S. Weissmann C. Aguzzi A. Nature. 1996; 379: 339-343Crossref PubMed Scopus (718) Google Scholar). Furthermore, in a transgenic mouse expressing a neurotoxic PrP mutant (3AV) with enhanced transmembrane topology, coexpression of wild-type PrPC contributes to disease progression (Stewart and Harris, 2005Stewart R.S. Harris D.A. J. Biol. Chem. 2005; 280: 15855-15864Crossref PubMed Scopus (45) Google Scholar). However, the neurotoxicity of several other mutant forms of PrP is antagonized effectively by wild-type PrPC. Currently, there is no convincing theoretical framework (including the one sketched by Chakrabarti and Hegde) that can reconcile these observations. So how might the results of Chakrabarti and Hegde instruct our understanding of neurotoxicity in prion infections? As the authors note, there is an increase in ER stress markers during prion infection, suggesting a vicious circle: misfolded PrP generated during prion infection may escape from the ER and enter the cytosol via a pre-emptive quality control pathway described in previous work by Hegde and colleagues. This may lead to mahogunin inactivation and other untoward events including lipid membrane disruption and proteasome inhibition, which may favor the accumulation of cyPrP and prion pathogenesis. Two key experiments are needed to directly test the relevance of the mahogunin-cyPrP connection to prion diseases. First, if cyPrP is a significant contributor to pathogenesis in the infectious forms of prion disease, one might expect prion infection to be synergistic with cyPrP. Hence, mice expressing cyPrP should experience aggravated pathogenesis after prion infection. However, transgenic cyPrP expression shortened the latency of disease by only ∼15 days in mice infected with the RML prion strain (which is marginal at best) and not at all with a different strain, 22L (W. Jackson, A.D.S., and S. Lindquist, unpublished data). Second, if prion toxicity is mediated primarily by mahogunin, one might expect mahoganoid mice (which are not healthy yet live long enough for the purpose of this experiment) to become paradoxically resistant to prion infection. However, the presence of the mahoganoid mutation did not modulate the progress of RML prion infection (G. Carlson and G. Barsh, personal communication). These unpublished results suggest that the mahogunin-cyPrP connection may be less crucial for bone fide prion infection, or that mahogunin depletion might be compensated for by other mechanisms. Conversely, certain familial forms of human prion disease are associated with only small amounts of PrPSc but with increased amounts of CtmPrP and are more likely to fit the mechanism described by Chakrabarti and Hegde. In the long run, small molecules that target the mahogunin-cyPrP interaction may provide plausible therapeutic leads for treating the unfortunate families afflicted with these hereditary prion diseases. A.A. is supported by the Swiss National Foundation, European Union FP7, and the Stammbach Foundation. A.D.S. is supported by the Broad Fellows in Brain Circuitry program at Caltech. Functional Depletion of Mahogunin by Cytosolically Exposed Prion Protein Contributes to NeurodegenerationChakrabarti et al.CellJune 12, 2009In BriefThe pathways leading from aberrant Prion protein (PrP) metabolism to neurodegeneration are poorly understood. Some familial PrP mutants generate increased CtmPrP, a transmembrane isoform associated with disease. In other disease situations, a potentially toxic cytosolic form (termed cyPrP) might be produced. However, the mechanisms by which CtmPrP or cyPrP cause selective neuronal dysfunction are unknown. Here, we show that both CtmPrP and cyPrP can interact with and disrupt the function of Mahogunin (Mgrn), a cytosolic ubiquitin ligase whose loss causes spongiform neurodegeneration. Full-Text PDF Open Archive" @default.
• W2077887509 created "2016-06-24" @default.
• W2077887509 creator A5012897375 @default.
• W2077887509 creator A5026438561 @default.
• W2077887509 date "2009-06-01" @default.
• W2077887509 modified "2023-09-26" @default.
• W2077887509 title "Prion Topology and Toxicity" @default.
• W2077887509 cites W1993198483 @default.
• W2077887509 cites W1998038512 @default.
• W2077887509 cites W2022094838 @default.
• W2077887509 cites W2063960399 @default.
• W2077887509 cites W2070579053 @default.
• W2077887509 cites W2077404304 @default.
• W2077887509 cites W2111426001 @default.
• W2077887509 cites W2154336998 @default.
• W2077887509 doi "https://doi.org/10.1016/j.cell.2009.05.041" @default.
• W2077887509 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19524502" @default.
• W2077887509 hasPublicationYear "2009" @default.
• W2077887509 type Work @default.
• W2077887509 sameAs 2077887509 @default.
• W2077887509 citedByCount "12" @default.
• W2077887509 countsByYear W20778875092012 @default.
• W2077887509 countsByYear W20778875092013 @default.
• W2077887509 countsByYear W20778875092014 @default.
• W2077887509 countsByYear W20778875092016 @default.
• W2077887509 countsByYear W20778875092017 @default.
• W2077887509 countsByYear W20778875092022 @default.
• W2077887509 countsByYear W20778875092023 @default.
• W2077887509 crossrefType "journal-article" @default.
• W2077887509 hasAuthorship W2077887509A5012897375 @default.
• W2077887509 hasAuthorship W2077887509A5026438561 @default.
• W2077887509 hasBestOaLocation W20778875091 @default.
• W2077887509 hasConcept C54355233 @default.
• W2077887509 hasConcept C70721500 @default.
• W2077887509 hasConcept C86803240 @default.
• W2077887509 hasConceptScore W2077887509C54355233 @default.
• W2077887509 hasConceptScore W2077887509C70721500 @default.
• W2077887509 hasConceptScore W2077887509C86803240 @default.
• W2077887509 hasIssue "6" @default.
• W2077887509 hasLocation W20778875091 @default.
• W2077887509 hasLocation W20778875092 @default.
• W2077887509 hasOpenAccess W2077887509 @default.
• W2077887509 hasPrimaryLocation W20778875091 @default.
• W2077887509 hasRelatedWork W1920751942 @default.
• W2077887509 hasRelatedWork W1990804418 @default.
• W2077887509 hasRelatedWork W1991523530 @default.
• W2077887509 hasRelatedWork W2002128513 @default.
• W2077887509 hasRelatedWork W2020824267 @default.
• W2077887509 hasRelatedWork W2031436818 @default.
• W2077887509 hasRelatedWork W2057739827 @default.
• W2077887509 hasRelatedWork W2075354549 @default.
• W2077887509 hasRelatedWork W2082860237 @default.
• W2077887509 hasRelatedWork W2092874662 @default.
• W2077887509 hasVolume "137" @default.
• W2077887509 isParatext "false" @default.
• W2077887509 isRetracted "false" @default.
• W2077887509 magId "2077887509" @default.
• W2077887509 workType "article" @default.