Utilize este identificador para referenciar este registo:
https://hdl.handle.net/1822/62019
Registo completo
Campo DC | Valor | Idioma |
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dc.contributor.author | Williamson, Rebecca L. | por |
dc.contributor.author | Laulagnier, Karine | por |
dc.contributor.author | Miranda, André M. | por |
dc.contributor.author | Fernandez, Marty A. | por |
dc.contributor.author | Wolfe, Michael S. | por |
dc.contributor.author | Sadoul, Rémy | por |
dc.contributor.author | Di Paolo, Gilbert | por |
dc.date.accessioned | 2019-11-11T13:48:57Z | - |
dc.date.available | 2019-11-11T13:48:57Z | - |
dc.date.issued | 2017 | - |
dc.identifier.issn | 0021-9258 | - |
dc.identifier.uri | https://hdl.handle.net/1822/62019 | - |
dc.description.abstract | Amyloid plaques, a neuropathological hallmark of Alzheimer's disease, are largely composed of amyloid β (Aβ) peptide, derived from cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The endosome is increasingly recognized as an important crossroad for APP and these secretases, with major implications for APP processing and amyloidogenesis. Among various post-translational modifications affecting APP accumulation, ubiquitination of cytodomain lysines may represent a key signal controlling APP endosomal sorting. Here, we show that substitution of APP C-terminal lysines with arginine disrupts APP ubiquitination and that an increase in the number of substituted lysines tends to increase APP metabolism. An APP mutant lacking all C-terminal lysines underwent the most pronounced increase in processing, leading to accumulation of both secreted and intracellular Aβ40. Artificial APP ubiquitination with rapalog-mediated proximity inducers reduced Aβ40 generation. A lack of APP C-terminal lysines caused APP redistribution from endosomal intraluminal vesicles (ILVs) to the endosomal limiting membrane, with a subsequent decrease in APP C-terminal fragment (CTF) content in secreted exosomes, but had minimal effects on APP lysosomal degradation. Both the increases in secreted and intracellular Aβ40 were abolished by depletion of presenilin 2 (PSEN2), recently shown to be enriched on the endosomal limiting membrane compared with PSEN1. Our findings demonstrate that ubiquitin can act as a signal at five cytodomain-located lysines for endosomal sorting of APP. They further suggest that disruption of APP endosomal sorting reduces its sequestration in ILVs and results in PSEN2-mediated processing of a larger pool of APP-CTF on the endosomal membrane. | por |
dc.description.sponsorship | This work was supported in part by National Institutes of Health Grants R01 NS056049 (to G. D. P. and Ronald Liem), F30 AG047748 (to R. L. W.), and AG015379 (to M. S. W. and Dennis J. Selkoe). | por |
dc.language.iso | eng | por |
dc.publisher | American Society for Biochemistry and Molecular Biology | por |
dc.rights | openAccess | por |
dc.subject | Amyloid beta-Peptides | por |
dc.subject | Amyloid beta-Protein Precursor | por |
dc.subject | Arginine | por |
dc.subject | Cell Line | por |
dc.subject | Endosomes | por |
dc.subject | Humans | por |
dc.subject | Lysine | por |
dc.subject | Mutation | por |
dc.subject | Peptide Fragments | por |
dc.subject | Presenilin-2 | por |
dc.subject | Proteolysis | por |
dc.subject | Ubiquitination | por |
dc.subject | Alzheimer disease | por |
dc.subject | amyloid precursor protein (APP) | por |
dc.subject | amyloid- (A) | por |
dc.subject | endosome | por |
dc.subject | intracellular processing | por |
dc.subject | intracellular trafficking | por |
dc.subject | lysosome | por |
dc.subject | presenilin | por |
dc.title | Disruption of amyloid precursor protein ubiquitination selectively increases amyloid β (Aβ) 40 levels via presenilin 2-mediated cleavage | por |
dc.type | article | por |
dc.peerreviewed | yes | por |
oaire.citationStartPage | 19873 | por |
oaire.citationEndPage | 19889 | por |
oaire.citationIssue | 48 | por |
oaire.citationVolume | 292 | por |
dc.identifier.eissn | 1083-351X | - |
dc.identifier.doi | 10.1074/jbc.M117.818138 | por |
dc.identifier.pmid | 29021256 | por |
dc.subject.wos | Science & Technology | por |
sdum.journal | Journal of Biological Chemistry | por |
Aparece nas coleções: | ICVS - Artigos em revistas internacionais / Papers in international journals |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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Williamson-2017-Disruption-of-amyloid-precursor-pro.pdf | 3,81 MB | Adobe PDF | Ver/Abrir |