Diabetes-Associated SorCS1 Regulates Alzheimer's Amyloid- Metabolism: Evidence for Involvement of SorL1 and the Retromer Complex

Department of Neurology and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2010; 30(39):13110-5. DOI: 10.1523/JNEUROSCI.3872-10.2010
Source: PubMed

ABSTRACT SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer's disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SORCS1 is also genetically associated with types 1 and 2 diabetes mellitus (T1DM, T2DM). We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer's amyloid-β peptide (Aβ) and the Aβ precursor protein (APP), to test the hypothesis that Sorcs1 deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1cβ-myc in cultured cells caused a reduction (p = 0.002) in Aβ generation. Conversely, endogenous murine Aβ(40) and Aβ(42) levels were increased (Aβ(40), p = 0.044; Aβ(42), p = 0.007) in the brains of female Sorcs1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SORCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1cβ-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% (p = 0.009) and total SorL1 protein levels were decreased by 29% (p = 0.003) in the brains of female Sorcs1 hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/Aβ disturbance underlying AD and the insulin/glucose disturbance underlying DM.

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Available from: James J Lah, Jan 27, 2014
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    • "These included the synaptic adhesion molecules Nlgn1 and Nlgn3 (Figure 4C, 4D, and S4A; Table S2), and the AMPAR subunit Gria2 (GluA2) (Figure 4C and S4A; Table S2). Various other receptors were also present, including members of the Plexin semaphorin receptor family, the previously identified SorCS1 interactor amyloid precursor protein (APP) (Lane et al., 2010), and Ntrk2 (TrkB), the receptor for the neurotrophin BDNF (Table S2). The results from the SorCS1 ectodomain interactome analysis suggest that SorCS1 interacts with multiple receptors and may regulate key synaptic functions. "
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    ABSTRACT: The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 08/2015; 87(4):764-80. DOI:10.1016/j.neuron.2015.08.007 · 15.05 Impact Factor
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    • "Certain IDE genotypes are related to a higher risk of diabetes (Fakhrai-Rad et al., 2000; Karamohamed et al., 2003; Kwak et al., 2008; Rudovich et al., 2009), although the contribution of IDE to diabetes is controversial (Groves et al., 2003) and other studies have found no relationship (Florez et al., 2006; Qin and Jia, 2008). SORCS1 may also affect insulin levels and the risk of diabetes (Clee et al., 2006; Goodarzi et al., 2007; Lane et al., 2010). Diabetes and insulin resistance are also more prevalent in persons with Down syndrome (Fonseca et al., 2005). "
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    Neurobiology of aging 06/2015; 36(10). DOI:10.1016/j.neurobiolaging.2015.06.020 · 5.01 Impact Factor
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    • "Retromer was first identified to sort VPS10 from endosome back to the TGN in yeast [123]. Recent studies have identified some retromer interacting proteins including SORL1 [124] and BACE1 [125]. Suppression of VPS35 expression decreases BACE1 trans-Golgi localization and retains BACE1 in the endosome, the optimal environment for BACE1 activity. "
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