SORL1

Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene.^[5]

SORL1 (also known as SORLA, SORLA1, or LR11; SORLA or SORL1 are used, often interchangeably, for the protein product of the SORL1 gene) is a 2214 residue

Retromer regulates protein trafficking from the early endosome either back to the trans-Golgi (retrograde) or back to the plasma membrane (direct recycling).[10] Two forms of retromer are known: the VPS26A retromer and the VPS26B retromer, the latter being dedicated to direct recycling in the CNS.^[11] SORL1 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.^[12]

The age at onset of SORL1 mutation carriers varies, which has complicated segregation analyses. Nevertheless, protein−truncating variants (PTVs) are observed almost exclusively in AD patients,^[13] indicating that SORL1 is haploinsufficient.^[14] However, most variants are rare missense variants that can be benign, or risk−increasing, but recent reports have indicated that some variants are causative for disease.^[15][16] In fact, specific missense variants have been observed only in AD cases, some of which may have a dominant negative effect.^[17].[1] [2]

ALZFORUM has created an interactive web page that maps all of the currently known variants onto the schematic of the SORLA domain structure shown in the Figure on the right, along with information for each one. It can be accessed at https://www.alzforum.org/mutations/sorl1

Clinical significance

A significant reduction in SORL1 (LR11)

• APP
• Presenilin
• GRIA1
• Retromer
• VPS26B
• VPS26A
• Endosome
• Protein targeting
• Lysosome
• Alzheimer's disease

References