Sortilin-related receptor

SORLA, is a 2214 residue type I transmembrane protein.

SORLA a is receptor that binds certain peptides and integral membrane protein cargo in the endolysosomal pathway and delivers them for sorting to the retromer protein complex. SORL1 is predominantly expressed in the central nervous system. Endosomal traffic jams linked to SORL1 retromer dysfunction are the earliest cellular pathology in both familial and the more common sporadic Alzheimer's disease.

Retromer regulates protein trafficking from the early endosome either back to the trans-Golgi (retrograde) or back to the plasma membrane (direct recycling). Two forms of retromer are known: the VPS26A retromer and the VPS26B retromer, the latter being dedicated to direct recycling in the CNS. SORLA is a multi domain single-pass membrane protein whose large ectodomain resides primarily in endosomal tubules, being connected by its transmembrane helical domain and cytoplasmic tail to the VPS26 retromer subunit on the outer endosomal membrane.

The age at onset of SORL1 mutation carriers varies, which has complicated segregation analyses. Nevertheless, protein−truncating variants are observed almost exclusively in AD patients, indicating that SORL1 is haploinsufficient. Most variants are rare missense variants that can either be benign, or risk−increasing, but studies have indicated that some variants are causative for disease. Specific missense variants have been observed only in AD cases, some of which may have a dominant negative effect.

A significant reduction in SORL1 expression has been found in brain tissue affected by Alzheimer's disease. Protein levels of retromer subunits have also been found to be reduced in the transentorhinal cortex, the brain region where Alzheimer's disease begins. SORL1-VPS26B retromer has been linked with regulation of amyloid precursor protein (APP), faulty processing of which is implicated in Alzheimer's. SORL1 cargo includes APP and its amyloid forming peptide cleavage products, as well as the important glutamate neurotransmitter receptor subunit GRIA1. SORL1 binds these and other cargo proteins and delivers them to the retromer, an assembly of multiple gene products that is the master regulator of protein trafficking from the early endosome. Studies by a group of international researchers support the proposition that SORL1 plays a part in seniors developing Alzheimer's disease, the findings being significant across racial and ethnic strata. SORL1 is now considered the fourth causal Alzheimer's gene, the others being APP and the two presenilins PSEN1 and PSEN2 and it is the only one also genetically linked to the common, late-onset sporadic form of the disease. Defective SORL1-retromer protein recycling has been proposed as the "fire" of sporadic Alzheimer's disease that drives production of amyloid and tau tangle "smoke", thereby resolving the apparent paradoxical failure of treatments aimed at the latter two to completely arrest the disease.