The sortilin-related receptor SORLA is an endocytic receptor that belongs to the vacuolar protein sorting 10 (VPS10) domain receptor family. SORLA binds to the amyloid precursor protein (APP). It functions as an intracellular sorting receptor as APP is being trafficked between the secretory pathway, the cell surface, and, subsequently, endosomes. SORLA is localized primarily to the trans-Golgi network and early endosomes, shuttling between these two membrane compartments. SORLA’s interaction with APP in endosomal compartments limits the amyloidogenic proteolysis of APP. Reduced brain levels of SORLA are thought to alter the transport and processing of APP to increase generation of Aβ peptides in early or late endosomes.
SORLA is highly expressed in the brain. Expression is reported to be normal in familial Alzheimer's disease caused by mutations in presenilin or APP genes, but decreased in some cases of sporadic late-onset AD. In these cases, loss of SORLA activity has been hypothesized to be a proximal cause of amyloidosis. In addition, several private nonsense and missense mutations in SORLA that decrease SORLA levels in the brain were found in rare cases of familial AD.
A genetic association of SORLA with AD is well established. Population-based studies initially linked nearly 30 SNPs in SORLA to increased risk of AD, and subsequent studies, meta-analyses, and GWAS have confirmed some of these associations. The genetic data on SORLA and LOAD is complex, with at least six different polymorphisms pointing toward the existence of several causative variants in distinct regions of the gene.
Several SORLA variants associated with AD have been reported to result in reduced SORLA protein levels, though overall regulation of SORLA expression is only partially understood. CSF biomarker studies of SORLA are inconclusive, with some but not all studies showing reduction in LOAD.
In addition to being a sorting receptor, SORLA has structural features of lipoprotein receptors, particularly the low-density lipoprotein (LDL) receptor family. It therefore may affect AD risk through its effects on lipoprotein signaling pathways, especially those involving the LDLR ligand apolipoprotein E. Besides ApoE, ligands that interact with SORLA’s extracellular portion include the growth factors GDNF and BDNF; however, the relevance, if any, of this binding to AD is unknown.
As a type-1 transmembrane protein, SORLA can undergo regulated intramembrane proteolysis and in the process shed a soluble ectodomain, but the physiological relevance of this fragment is unclear.
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