[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.
[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.
[11][20] SORL1 cargo includes APP and its amyloid forming peptide cleavage products, as well as the important glutamate neurotransmitter receptor subunit GRIA1.
[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.
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-zgbg4
A 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.
