Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein
dc.contributor.author | Karaca, I | |
dc.contributor.author | Tamboli, IY | |
dc.contributor.author | Glebov, Konstantin | |
dc.contributor.author | Richter, J | |
dc.contributor.author | Fell, LH | |
dc.contributor.author | Grimm, MO | |
dc.contributor.author | Haupenthal, VJ | |
dc.contributor.author | Hartmann, T | |
dc.contributor.author | Gräler, MH | |
dc.contributor.author | van Echten-Deckert, G | |
dc.contributor.author | Walter, J | |
dc.date.accessioned | 2019-01-30T12:52:57Z | |
dc.date.available | 2019-01-30T12:52:57Z | |
dc.date.issued | 2014-06 | |
dc.identifier.issn | 0021-9258 | |
dc.identifier.issn | 1083-351X | |
dc.identifier.uri | http://hdl.handle.net/10026.1/13245 | |
dc.description.abstract |
Progressive accumulation of the amyloid β protein in extracellular plaques is a neuropathological hallmark of Alzheimer disease. Amyloid β is generated during sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. In addition to the proteolytic processing by secretases, APP is also metabolized by lysosomal proteases. Here, we show that accumulation of intracellular sphingosine-1-phosphate (S1P) impairs the metabolism of APP. Cells lacking functional S1P-lyase, which degrades intracellular S1P, strongly accumulate full-length APP and its potentially amyloidogenic C-terminal fragments (CTFs) as compared with cells expressing the functional enzyme. By cell biological and biochemical methods, we demonstrate that intracellular inhibition of S1P-lyase impairs the degradation of APP and CTFs in lysosomal compartments and also decreases the activity of γ-secretase. Interestingly, the strong accumulation of APP and CTFs in S1P-lyase-deficient cells was reversed by selective mobilization of Ca(2+) from the endoplasmic reticulum or lysosomes. Intracellular accumulation of S1P also impairs maturation of cathepsin D and degradation of Lamp-2, indicating a general impairment of lysosomal activity. Together, these data demonstrate that S1P-lyase plays a critical role in the regulation of lysosomal activity and the metabolism of APP. | |
dc.format.extent | 16761-16772 | |
dc.format.medium | Print-Electronic | |
dc.language | en | |
dc.language.iso | eng | |
dc.publisher | Elsevier BV | |
dc.subject | Alzheimer Disease | |
dc.subject | Amyloid | |
dc.subject | Amyloid Precursor Protein (APP) | |
dc.subject | Lysosome | |
dc.subject | Sphingolipid | |
dc.subject | Sphingosine-1-phosphate (S1P) | |
dc.subject | Aldehyde-Lyases | |
dc.subject | Amyloid Precursor Protein Secretases | |
dc.subject | Amyloid beta-Protein Precursor | |
dc.subject | Animals | |
dc.subject | Calcium | |
dc.subject | Cathepsin D | |
dc.subject | HEK293 Cells | |
dc.subject | Humans | |
dc.subject | Lysophospholipids | |
dc.subject | Lysosomal-Associated Membrane Protein 2 | |
dc.subject | Lysosomes | |
dc.subject | Mice | |
dc.subject | Proteolysis | |
dc.subject | Sphingosine | |
dc.title | Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein | |
dc.type | journal-article | |
dc.type | Journal Article | |
dc.type | Research Support, Non-U.S. Gov't | |
plymouth.author-url | https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000338016200015&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008 | |
plymouth.issue | 24 | |
plymouth.volume | 289 | |
plymouth.publication-status | Published | |
plymouth.journal | Journal of Biological Chemistry | |
dc.identifier.doi | 10.1074/jbc.m113.535500 | |
plymouth.organisational-group | /Plymouth | |
plymouth.organisational-group | /Plymouth/Faculty of Health | |
plymouth.organisational-group | /Plymouth/Faculty of Health/Peninsula Medical School | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine | |
plymouth.organisational-group | /Plymouth/Users by role | |
plymouth.organisational-group | /Plymouth/Users by role/Academics | |
dc.publisher.place | United States | |
dc.identifier.eissn | 1083-351X | |
dc.rights.embargoperiod | Not known | |
rioxxterms.versionofrecord | 10.1074/jbc.m113.535500 | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.type | Journal Article/Review |