Deficiency of sphingosine-1-phosphate lyase impairs lysosomal metabolism of the amyloid precursor protein [Lipids]

May 7th, 2014 by Karaca, I., Tamboli, I. Y., Glebov, K., Richter, J., Fell, L. H., Grimm, M. O., Haupenthal, V. J., Hartmann, T., Graler, M. H., van Echten–Deckert, G., Walter, J.

Progressive accumulation of the amyloid β (Aβ) protein in extracellular plaques is a neuropathological hallmark of Alzheimer disease. Aβ 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 to 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 Ca2+ 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.