SUBCELLULAR ROUTING OF SORTILIN AND SORLA

Sortilin and SorLA (also named SORL1) are type 1 single-pass membrane sorting receptors that share the defining N-terminal Vps10p-domain. In Sortilin, the Vps10p-domain constitutes the entire ectodomain while the luminal part of SorLA has additional domains such as LDL receptor-related domains. Both receptors are predominantly expressed in the developing and adult nervous system and participate in endocytic and intracellular trafficking pathways. Sortilin plays a central role in regulating progranulin levels and is considered a pharmacological target in frontotemporal lobar degeneration (FTLD). SorLA binds multiple ligands including the amyloid precursor protein (APP) and is thought to play a protective role in Alzheimer´s disease by regulating APP trafficking and reducing amyloid-β (Aβ) generation.
The functions of monomeric forms of both receptors have been extensively studied, whereas much less is known about their dimerization. Homodimerization of Sortilin and SorLA is thought to modulate the receptor function, such as ligand-binding. Biophysical evidence support that Sortilin dimerizes via its ectodomain in acidic intracellular compartments, although this has not yet been conclusively demonstrated in cells under physiological conditions. In contrast dimerization of SorLA remains less well understood, as specific domains and subcellular sites mediating dimerization have not been fully described.
Having established biological tools for visualization and detailed analysis of dimerization, we employ protein interaction assays and imaging approaches to validate homodimerization of both receptors under physiological conditions. Studying the trafficking of monomeric and dimeric Sortilin and SorLA, we aim to gain mechanistic insights of receptor function in the context of AD.