title: Deficiency of sphingosine-1-phosphate lyase impairs lysosomal metabolism of the amyloid precursor protein.
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.
authors.affiliation: From the Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Ilker
authors.initials: I
authors.lastname: Karaca
authors.affiliation: From the Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Irfan Y
authors.initials: IY
authors.lastname: Tamboli
authors.affiliation: From the Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Glebov
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany.
authors.forename: Josefine
authors.initials: J
authors.lastname: Richter
authors.affiliation: the Department of Experimental Neurology, University of the Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Fell
authors.affiliation: the Department of Experimental Neurology, University of the Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Grimm
authors.affiliation: the Department of Experimental Neurology, University of the Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Viola J
authors.initials: VJ
authors.lastname: Haupenthal
authors.affiliation: the Department of Experimental Neurology, University of the Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
authors.affiliation: the Department of Anaesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care, and Center for Molecular Biomedicine, University Hospital Jena, 07740 Jena, Germany, and.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Gräler
authors.affiliation: the Life and Medical Sciences, Membrane Biology and Lipid Biochemistry Unit at the Kekulé-Institute, University of Bonn, 53121 Bonn, Germany.
authors.forename: Gerhild
authors.initials: G
authors.lastname: van Echten-Deckert
authors.affiliation: From the Department of Neurology, University of Bonn, 53127 Bonn, Germany, Jochen.Walter@ukb.uni-bonn.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
mesh_terms: D000446:Aldehyde-Lyases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D059748:Proteolysis; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D008246:Lysophospholipids; D052119:Lysosomal-Associated Membrane Protein 2; C060506:sphingosine 1-phosphate; D053829:Amyloid Precursor Protein Secretases; D002402:Cathepsin D; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine; D002118:Calcium
keywords: Alzheimer Disease; Amyloid; Amyloid Precursor Protein (APP); Lysosome; Sphingolipid; Sphingosine-1-phosphate (S1P)