Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein

Karaca, Ilker; Tamboli, Irfan Y.; Glebov, Konstantin; Richter, Josefine; Fell, Lisa H.; Grimm, Marcus O.W.; Haupenthal, Viola J.; Hartmann, Tobias; Gräler, Markus H.; Echten‐Deckert, Gerhild van; Walter, Jochen

doi:10.1074/jbc.m113.535500

Cited by 54 publications

(52 citation statements)

References 59 publications

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“…2A ). This is in agreement with a previous report ( 29 ). In addition, the concentrations of sphingosine in the supernatants were similar in both cells types ( Fig.…”

Section: Immunocytochemistrysupporting

confidence: 82%

“…Interestingly, although nearly all known S1P transporters were upregulated in Sgpl1 Ϫ / Ϫ -MEFs, we did not observe altered concentrations of S1P or sphingosine in the cellular supernatants, in line with data from Karaca et al ( 29 ). Even when high concentrations of potential acceptors for the lipids were added to the supernatants (i.e., 10 mg/ml BSA or 10% FCS), there was no enhanced secretion of [ ]sphingosine from S1P lyase-defi cient MEFs.…”

Section: Downloaded Fromsupporting

confidence: 79%

“…( 38 ). It is tempting to speculate that there is a general membrane transport defect in S1P lyase-defi cient MEFs, as amyloid precursor protein processing is also impaired in these cells ( 29 ), but the observed effects could also be due to altered Rab signaling and/or defective recycling of the multidrug transporters.…”

Section: Downloaded Frommentioning

confidence: 99%

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Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts

Ihlefeld

Vienken

Claas

et al. 2015

Journal of Lipid Research

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“…2A ). This is in agreement with a previous report ( 29 ). In addition, the concentrations of sphingosine in the supernatants were similar in both cells types ( Fig.…”

Section: Immunocytochemistrysupporting

confidence: 82%

Section: Downloaded Fromsupporting

confidence: 79%

See 1 more Smart Citation

Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts

Ihlefeld

Vienken

Claas

et al. 2015

Journal of Lipid Research

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“…Thus, we used previously described fibroblasts that express either APP-WT or the familial Alzheimer disease-associated Swedish mutant variant of APP (APP-SW) (30). As expected, levels of A␤ in conditioned media from cells expressing the APP-SW variant were much higher than that in media from APP-WTexpressing cells (Fig.…”

Section: Trehalose Impairs the Metabolism Of App And Decreases The Sementioning

confidence: 99%

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

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The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, ␣-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-␤ peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport.Alzheimer disease is characterized by the accumulation of extracellular amyloid plaques that contain aggregates of the amyloid ␤-peptide (A␤).5 A␤ is derived from the amyloid precursor protein by sequential proteolytic processing by ␤-and ␥-secretases (1, 2). The initial cleavage of amyloid precursor protein (APP) by ␤-secretase results in the secretion of the soluble ectodomain and the generation of a membrane-tethered C-terminal fragment (APP-CTF␤). Subsequently, APP-CTF␤ can be cleaved by ␥-secretase to liberate A␤ from cellular membranes (2). In an alternative pathway, APP can also be cleaved by ␣-secretase within the A␤ domain, thereby generating CTF␣. The subsequent cleavage of APP-CTF␣ by ␥-secretase results in secretion of a small peptide called p3 (2). It is important to note that APP is also metabolized by additional pathways, including proteasomal and lysosomal degradation (3-5).The metabolism of APP is also regulated by macroautophagy (herein referred to as autophagy), a lysosome-dependent degradative pathway for long lived proteins, organelles, and nutrient recycling (6, 7). Autophagy starts with the formation of double-membrane vesicles, the so-called autophagosomes, which further fuse with lysosomes to become autolysosomes for degradation of autophagosome contents by lysosomal hydrolases (8). Autophagy is an essential prosurvival pathway induced by a variety of stress factors, including nutrient deprivation, growth factor withdrawal, oxidative stress, infection, and hypoxia (9). These factors contribute to the etiology of multiple diseases such as cancer, stroke, heart disease, and infection (10). Eukaryotic cells have a basal autophagic activity under normal physiological conditions. Cells deficient in autophagy show diffuse abnormal protein accumulation and mitochondrial disorganization (11,12), suggesting that autophagy is important to maintain cellular homeostasis by eliminating protein aggregates and damaged organelles. Basal ...

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“…7, G-I, one-way ANOVA, p Ͻ 0.05). We also used Western blot to compare the protein levels of LAMP-1 and Gm2A, which are degraded by lysosomes (42), in p38␣ MAPKdeficient and wild-type SH-SY5Y cells. As shown in Fig.…”

Section: Knockdown Of P38␣ Mapk Expression Does Not Change the Phosphmentioning

confidence: 99%

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

Schnöder

Hao

Qin

et al. 2016

Journal of Biological Chemistry

111

123

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Amyloid ␤ (A␤) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in A␤ generation. Neuroinflammation potentially up-regulates BACE1 expression and increases A␤ production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38␣ MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38␣ MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated A␤ generation in the AD mouse brain. Inhibition of p38␣ MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38␣ MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38␣ MAPK plays a critical role in the regulation of BACE1 degradation and A␤ generation in AD pathogenesis. Alzheimer disease (AD)2 is pathologically characterized by the extracellular deposits of amyloid ␤ peptide (A␤). A␤ injures neurons in the neocortex and limbic system directly (1) and indirectly by triggering microglial release of various neurotoxic inflammatory mediators, including cytokines (tumor necrosis factor-␣ and interleukin-1␤ (IL-1␤)) and reactive oxygen species (2). A␤ is generated after serial digestion of Alzheimer amyloid precursor protein (APP) by the membrane-anchored ␤-site APP-cleaving enzyme (BACE1, ␤-secretase) and ␥-secretase (3). It has been observed that knock-out of BACE1 or administration of the BACE1 inhibitor dramatically decreases A␤ levels in the brain and attenuates behavioral and electrophysiological deficits in APP-transgenic mice (4 -6). Thus, extensive investigations have focused on the direct inhibition of BACE1 to reduce A␤ load in the AD brain; however, these studies have unfortunately not yet led to any efficacious therapy for AD patients due to the various physiological roles of BACE1 (7). Using alternative methods to inhibit BACE1 might be a preferable investigative approach.Inflammatory activation might lead to up-regulation of neuronal BACE1 expression in the AD brain, as NF-B signaling enhances (8), and PPAR␥ activation suppresses (9), the activity of bace1 gene promoter. Accumulating evidence has shown that posttranslational modification of BACE1 is extremely important for the activity, intracellular trafficking, and lysosomal degradation of BACE1. For example, phosphorylation of BACE1 at Thr-252 by p25/Cdk5 increases the secretase activity (10), and phosphorylation at Ser-498 facilitates retrograde transport of BACE1 from endosomes to the trans-Golgi network (11). Ubiquitination at Lys-501 targets BACE1 to late endosomes/lysosomes for degradation (12). Finally, bisecting N-acetylglucosamine modification blocks delivery of BACE1 to lysosomes (13).p38 mitogen-activated protei...

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Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein

Cited by 54 publications

References 59 publications

Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts

Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

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