Schematic diagram of the multiple domains of SORLA, the protein product of the SORL1 gene. The relative orientations of the domains are drawn to match the ectodomain model of Jensen et al., PNAS (2023), which is also shown on the next figure. From Holstege et al., medRxiv (2023).Schematic and structure model of the ectodomain of SORLA/SORL1, plus its two dimer interfaces in the middle panel, followed by the way the two interfaces can combine to form a polymeric network and how that network can underlie and stabilize the network of retromer arches on the other side of the tubular membrane. From Jensen et al., PNAS (2023). Atomic coordinates of the ectodomain model are available at https://modelarchive.org/doi/10.5452/ma-zgbg4A model of the endosome tubule showing the characteristic retromer arch polymer wrapping around the outer (cytoplasmic) side and the ectodomain of SORL1 forming a supporting polymeric network inside. The interior SORL1 network is anchored to retromer by a transmembrane helix and a short C-terminal domain that binds to VPS26 (dark green) on the outside.
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 type I transmembrane protein receptor that binds certain peptides and integral membrane protein cargo in the endolysosomal pathway and delivers them for sorting to the retromer multi protein complex;[6] the gene is predominantly expressed in the central nervous system.[7] Endosomal traffic jams linked to SORL1 retromer dysfunction are the earliest cellular pathology in both familial and the more common sporadic Alzheimer’s patients.[8][9]
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) expression has been found in brain tissue of Alzheimer's disease patients.[18] Protein levels of retromer subunits have also been found to be reduced in the transentorhinal cortex of sporadic Alzheimer’s patients, the brain region where Alzheimer’s disease begins.[19] SORL1-VPS26B retromer has been linked with regulation of amyloid precursor protein (APP), faulty processing of which is implicated in Alzheimer's.[11][20] SORL1 cargo includes APP and its amyloid forming peptide cleavage products, as well as the important glutamate neurotransmitter receptor subunit GRIA1.[21] 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.[22] 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.[23] SORL1 is now considered the fourth causal Alzheimer’s gene,[16] the others being APP and the two presenilins PSEN1 and PSEN2 [24] and it is the only one also genetically linked to the common, late-onset sporadic form of the disease.[25] 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.[26]
^Small SA, Petsko GA (March 2015). "Retromer in Alzheimer disease, Parkinson disease and other neurological disorders". Nature Reviews. Neuroscience. 16 (3): 126–132. doi:10.1038/nrn3896. PMID25669742. S2CID5166260.
^Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, et al. (August 2004). "Loss of apolipoprotein E receptor LR11 in Alzheimer disease". Archives of Neurology. 61 (8): 1200–1205. doi:10.1001/archneur.61.8.1200. PMID15313836. S2CID22176694.
^Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, et al. (December 2005). "Model-guided microarray implicates the retromer complex in Alzheimer's disease". Annals of Neurology. 58 (6): 909–919. doi:10.1002/ana.20667. PMID16315276. S2CID34144181.
