Disease relevance of SORL1

• Taken together, LR11, a mosaic LDLR family member whose expression in smooth muscle cells is markedly induced in atheroma, has all the properties of a receptor for the endocytosis of lipoproteins, particularly for the incorporation of apoE-rich lipoproteins [1].
• Furthermore, such proliferation-dependent expression of LR11 could be observed in a cultured neuroblastoma cell line, which was established to be a suitable in vitro model for proliferation and differentiation [2].

Psychiatry related information on SORL1

• SorLA has been shown to be down regulated in Alzheimer's disease brains, interact with ApoE, and modulate Abeta production [3].
• The SCOFF questions were less sensitive than predicted (1 or no abnormal responses, LR 0.25), but were as effective at ruling in an eating disorder (3 or more abnormal responses, LR 11) [4].
• These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease [5].

High impact information on SORL1

• We have found that a fraction of SorLA/LR11 that is synthesized in the kidney and the brain bears N-linked oligosaccharides that are modified with terminal beta1,4-linked GalNAc-4-SO(4) [6].
• SorLA/LR11 has features that indicate it serves as a sorting receptor shuttling between the plasma membrane, endosomes, and the Golgi [6].
• Sorting protein-related receptor (SorLA/LR11) is a highly conserved mosaic receptor that is expressed by cells in a number of different tissues including principal cells of the collecting ducts in the kidney and neurons in the central and peripheral nervous systems [6].
• In a reporter gene assay the cytoplasmic domain of SorLA acted as a transcriptional activator indicating that SorLA might directly regulate transcription after activation by gamma-secretase [7].
• The gene, designated SORL1, maps to chromosome 11q 23/24 and encodes a 2214-residue type 1 receptor containing a furin cleavage site immediately preceding the N terminus determined in the purified protein [8].

Biological context of SORL1

• Characterization of the VPS10 domain of SorLA/LR11 as binding site for the neuropeptide HA [9].
• Here, we show neuronal expression of the lipoprotein receptor LR11 in control brain in regions vulnerable to AD neuropathology and marked reduction of LR11 expression in these regions in AD brains before cell death [10].
• The expression of LR11, a member of the LDL receptor family and an enhancer of cell surface localization of urokinase-type plasminogen activator receptor (uPAR), is increased in cultured SMCs by treatment with PDGF-BB [11].
• Possible involvement of LR11 in the cellular proliferation sheds new light on the recently proposed novel functions of the LDL receptor gene family in atherosclerosis [2].

Anatomical context of SORL1

• The neuronal localization of LR11 and its unique association of cytoplasmic structure, presumably botrysome, may suggest the roles of LR11 in both the lipoprotein metabolism and intracellular trafficking in certain neuronal population of the CNS [12].
• Uniquely, the single LR11 immunoreactive cytoplasmic puncta were observed in the proximity of apical dendrites, most conspicuously in the pyramidal neurons of hippocampus [12].
• The predominant expression of LR11 transcripts in brain tissue and the presence of elements found in neural adhesion molecules suggested a function(s) in the central nervous system (CNS) [12].
• LR11 shows specific binding of apoE-enriched HDL prepared from human cerebrospinal fluid as well as of beta-VLDL, suggesting that the apoE content of lipoproteins is most likely important for mediating the high-affinity binding to the receptor [1].
• Thus, LR11 mediates the uPAR localization to the plasma membrane [13].

Associations of SORL1 with chemical compounds

• The increased migration of SMCs observed both upon overexpression of LR11 and via stimulation of secretion of soluble LR11 is not reversed by pitavastatin [11].

Regulatory relationships of SORL1

• SorLA/LR11 is a sorting receptor that regulates the intracellular transport and processing of the amyloid precursor protein (APP) in neurons [14].
• The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments [10].

Other interactions of SORL1

• Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11 [14].
• The robust correlation between reduced LR11 expression and AD neuropathology and its potent effects on extracellular Abeta levels suggest that this neuronal lipoprotein receptor could play an important role in AD pathogenesis [10].
• The single transmembrane receptor sorLA/LR11 contains binding domains typical for the low-density lipoprotein receptors and a VPS10 domain which, in the related receptor sortilin, binds the neuropeptide neurotensin [9].
• We hypothesized that 1 of the genes, termed low-density lipoprotein receptor relative with 11 binding repeats (LR11) (reduced 1.8- and 2.5-fold in AD lymphoblasts vs controls), might be associated with sporadic AD on the basis of its function as neuronal apolipoprotein E receptor [15].
• Sortilin, SorCS1b, and SorLA Vps10p sorting receptors, are novel gamma-secretase substrates [3].

Analytical, diagnostic and therapeutic context of SORL1

• This reduction of LR11 protein was confirmed by quantitative Western blotting (P =.01) [15].
• We have discovered that the expression of a 250-kDa mosaic LDLR-related protein, which we termed LR11 for the presence of 11 LDLR ligand-binding repeats, is markedly induced in smooth muscle cells in the hyperplastic intima of animal models used for the study of atherosclerosis [1].
• To determine whether these large puncta correspond to HAP1-containing SBs, we used antibodies specific to various domains of the apolipoprotein receptor LR11 to perform immunocytochemistry in rat and mouse brain tissue [16].
• Electron microscopy was performed in rat hypothalamus and further demonstrated the presence of LR11 in SBs and its co-localization with HAP1 [16].

References