Sortilin, SorCSIb, and SorLA Vps 10p sorting receptors, are novel γ-secretase substrates

Department of Neuroscience, Mayo Clinic Jacksonville, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
Molecular Neurodegeneration (Impact Factor: 6.56). 02/2006; 1(1):3. DOI: 10.1186/1750-1326-1-3
Source: PubMed


The mammalian Vps10p sorting receptor family is a group of 5 type I membrane homologs (Sortilin, SorLA, and SorCS1-3). These receptors bind various cargo proteins via their luminal Vps10p domains and have been shown to mediate a variety of intracellular sorting and trafficking functions. These proteins are highly expressed in the brain. SorLA has been shown to be down regulated in Alzheimer's disease brains, interact with ApoE, and modulate Abeta production. Sortilin has been shown to be part of proNGF mediated death signaling that results from a complex of Sortilin, p75NTR and proNGF. We have investigated and provide evidence for gamma-secretase cleavage of this family of proteins.
We provide evidence that these receptors are substrates for presenilin dependent gamma-secretase cleavage. Gamma-secretase cleavage of these sorting receptors is inhibited by gamma-secretase inhibitors and does not occur in PS1/PS2 knockout cells. Like most gamma-secretase substrates, we find that ectodomain shedding precedes gamma-secretase cleavage. The ectodomain cleavage is inhibited by a metalloprotease inhibitor and activated by PMA suggesting that it is mediated by an alpha-secretase like cleavage.
These data indicate that the alpha- and gamma-secretase cleavages of the mammalian Vps10p sorting receptors occur in a fashion analogous to other known gamma-secretase substrates, and could possibly regulate the biological functions of these proteins.

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    • "This is in line with the notion that small alterations in intracellular trafficking of APP are thought to have a modest impact on Ab generation and probably result as a long-term effect over a lifetime in dramatic Ab accumulation (Hermey 2011; Brunholz et al. 2012), supporting the hypothesis that SorCS1 plays a role in APP targeting. However, apart from the assumption that the genetic association of SorCS1 and AD is explained by an influence of SorCS1 on APP transport, it should be taken into consideration that SorCS1, and, interestingly, also SorLA, are substrates of the alpha and gamma secretase (Hermey et al. 2006; Nyborg et al. 2006). It is still unclear if sorting receptor interaction with APP competes for processing of APP by secretases, or if sorting receptors directly modulate trafficking and activity of secretases. "
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    ABSTRACT: Processing of amyloid precursor protein (APP) into amyloid-β peptide (Aβ) is crucial for the development of Alzheimer's disease (AD). Because this processing is highly dependent on its intracellular itinerary, altered subcellular targeting of APP is thought to directly affect the degree to which Aβ is generated. The sorting receptor SorCS1 has been genetically linked to AD, but the underlying molecular mechanisms are poorly understood. We analyze two SorCS1 variants; one, SorCS1c, conveys internalization of surface bound ligands whereas the other, SorCS1b, does not. In agreement with previous studies, we demonstrate co-immunoprecipitation and co-localization of both SorCS1 variants with APP. Our results suggest that SorCS1c and APP are internalized independently, although they mostly share a common postendocytic pathway. We introduce functional Venus-tagged constructs to study SorCS1b and SorCS1c in living cells. Both variants are transported by fast anterograde axonal transport machinery and about 30% of anterograde APP-positive transport vesicles contain SorCS1. Co-expression of SorCS1b caused no change of APP transport kinetics, but SorCS1c reduced the anterograde transport rate of APP and increased the number of APP-positive stationary vesicles. These data suggest that SorCS1 and APP share trafficking pathways and that SorCS1c can retain APP from insertion into anterograde transport vesicles. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 06/2015; 135(1). DOI:10.1111/jnc.13221 · 4.28 Impact Factor
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    • "and subsequently increase the progress of neurodegenerative diseases like AD (Nyborg et al. 2006; Lane et al. 2012). For example, sorLA and SORCS1 mediate retrograde trafficking of APP from the cell surface to Golgi compartments and reduce the amyloidergic processing of APP and production of Ab and decrease the risk of AD (Nyborg et al. 2006; "
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    ABSTRACT: Sortilin, a Golgi sorting protein and a member of the VPS10P family, is the co-receptor for proneurotrophins, regulates protein trafficking, targets proteins to lysosomes, and regulates low density lipoprotein metabolism. The aim of this study was to investigate the expression and regulation of sortilin in Alzheimer's disease (AD). A significantly increased level of sortilin was found in human AD brain and in the brains of 6-month-old swedish-amyloid precursor protein/PS1dE9 transgenic mice. Aβ42 enhanced the protein and mRNA expression levels of sortilin in a dose- and time-dependent manner in SH-SY5Y cells, but had no effect on sorLA. In addition, proBDNF also significantly increased the protein and mRNA expression of sortilin in these cells. The recombinant extracellular domain of p75NTR (P75ECD-FC), or the antibody against the extracellular domain of p75NTR, blocked the up-regulation of sortilin induced by Amyloid-β protein (Aβ), suggesting that Aβ42 increased the expression level of sortilin and mRNA in SH-SY5Y via the p75NTR receptor. Inhibition of ROCK, but not Jun N-terminal kinase, suppressed constitutive and Aβ42-induced expression of sortilin. In conclusion, this study shows that sortilin expression is increased in the AD brain in human and mice and that Aβ42 oligomer increases sortilin gene and protein expression through p75NTR and RhoA signaling pathways, suggesting a potential physiological interaction of Aβ42 and sortilin in Alzheimer's disease. Sortilin is the co-receptor of p75NTR which signals the cell death induced by Aβ and proneurotrophins. We found that sortilin is increased in the AD brain and up-regulated by Aβ and pro-brain-derived neurotrophic factor (proBDNF). Aβ-induced upregulation of sortilin is mediated by p75NTR and the down-streaming RhoA-ROCK signaling pathway. The Aβ/Sortilinp/75NTR signaling may play a role in the pathogenesis of AD.
    Journal of Neurochemistry 07/2013; 127(2). DOI:10.1111/jnc.12383 · 4.28 Impact Factor
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    • "Sortilin was first identified as a 95kDa intracellular sorting receptor that directs movements of newly synthesized proteins such as the unprocessed form of nerve growth factor (proNGF), neurotensin, lipoprotein lipase and pro-brain-derived neurotrophic factor (proBDNF) (Lin et al., 1997; Mazella et al., 1998; Munck Petersen et al., 1999; Nyborg et al., 2006; Nykjaer et al., 2004; Teng et al., 2005). Sortilin was also found to function as a larger 100 kDa receptor for these proteins once exposed on the cell surface, usually in concert with another receptor (Jansen et al., 2007). "
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    ABSTRACT: The common neurotrophin receptor P75NTR, its co-receptor sortilin and ligand proNGF, have not previously been investigated in Natural Killer (NK) cell function. We found freshly isolated NK cells express sortilin but not significant amounts of P75NTR unless exposed to interleukin-12 (IL-12), or cultured in serum free conditions, suggesting this receptor is sequestered. A second messenger associated with p75NTR, neurotrophin-receptor-interacting-MAGE-homologue (NRAGE) was identified in NK cells. Cleavage resistant proNGF123 killed NK cells in the presence of IL-12 after 20 h and without IL-12 in serum free conditions at 48 h. This was reduced by blocking sortilin with neurotensin. We conclude that proNGF induced apoptosis of NK cells may have important implications for limiting the innate immune response.
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