VPS10P Domain Receptors: Sorting Out Brain Health and Disease

Vacuolar protein sorting 10 protein (VPS10P) domain receptors are sorting receptors that determine the subcellular fate of multiple proteins central to functional integrity and pathophysiology of the brain. Although structurally related, VPS10P domain receptors are distinguished by ligand repertoire, as well as by distinct modes of ligand binding and release. A specific repertoire of cytosolic adaptors determines unique trafficking routes for each receptor through secretory and endocytic compartments of the cell. Alternative splicing, propeptide cleavage, and ectodomain shedding are regulatory processes that alter the structure and function of VPS10P domain receptors. Expression patterns of VPS10P domain receptors in the brain are highly dynamic and change during development as well as in response to acute or chronic insults to the nervous system. VPS10P (vacuolar protein sorting 10 protein) domain receptors are neuronal sorting receptors that direct cargo proteins to their destined location in subcellular compartments of the soma, dendrites, and the axon. Protein sorting by receptors such as SORLA, sortilin, and SorCS2 controls functional integrity and viability of neurons, whereas sorting receptor dysfunctions are linked to acute, psychiatric, and neurodegenerative diseases. Here, we discuss molecular mechanisms that define ligand repertoire and sorting path and that control plasticity of VPS10P domain receptor expression in the healthy brain and in response to injury. These findings highlight important concepts in neuronal protein sorting and why aberrant sorting contributes to the progression of devastating diseases of the human brain, including epilepsy, Alzheimer’s disease, and frontotemporal dementia. VPS10P (vacuolar protein sorting 10 protein) domain receptors are neuronal sorting receptors that direct cargo proteins to their destined location in subcellular compartments of the soma, dendrites, and the axon. Protein sorting by receptors such as SORLA, sortilin, and SorCS2 controls functional integrity and viability of neurons, whereas sorting receptor dysfunctions are linked to acute, psychiatric, and neurodegenerative diseases. Here, we discuss molecular mechanisms that define ligand repertoire and sorting path and that control plasticity of VPS10P domain receptor expression in the healthy brain and in response to injury. These findings highlight important concepts in neuronal protein sorting and why aberrant sorting contributes to the progression of devastating diseases of the human brain, including epilepsy, Alzheimer’s disease, and frontotemporal dementia. dynamic structure at the distal tip of an elongating neuronal axon, responsible for its guidance. the domain of a transmembrane protein extending from the plasma membrane into the extracellular space. extracellular vesicle formed by the release of the content of late endosomes into the extracellular space. secreted proteins promoting survival, development, and function of neurons by binding to neurotrophin receptors. a subtype of ionotropic glutamate receptor activated by NMDA. network of proteins within and adjacent to the postsynaptic membrane that constitutes the organizing center for synaptic receptors and effectors. precursor forms of neurotrophins containing an amino terminal pro-domain. amino terminal extension of a protein that is cleaved during maturation. proteolytic release of extracellular domains (ectodomains) of membrane-anchored proteins at the cell surface. a single nucleotide variation that occurs at a specific position in the genome. cytosolic proteins that direct transmembrane proteins to distinct subcellular compartments by interacting both with the tail of the target protein and the protein coat of target membranes.