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SORL1

Protein-coding gene in the species Homo sapiens

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.

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

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; the gene 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 patients.

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. 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.

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, indicating that SORL1 is haploinsufficient. 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. In fact, specific missense variants have been observed only in AD cases, some of which may have a dominant negative effect..https://www.alzforum.org/news/research-news/sorting-out-sorl1-500-mutations-mapped-prioritized-alzforum-dataset https://www.alzforum.org/news/research-news/when-missense-variants-derail-sorl1-traffic-destination-dementia

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. 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. 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.

References

"Entrez Gene: Sortilin-related receptor, L(DLR class) A repeats containing".
(March 2015). "Retromer in Alzheimer disease, Parkinson disease and other neurological disorders". Nature Reviews. Neuroscience.
(January 2022). "The role of Alzheimer's disease risk genes in endolysosomal pathways". Neurobiology of Disease.
(July 2000). "Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations". The American Journal of Pathology.
(October 2017). "Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer's Disease". Trends in Neurosciences.
(2023). "Receptor Recycling by Retromer". Molecular and Cellular Biology.
(December 2021). "Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling". Cell Reports.
(October 2012). "Vps10 family proteins and the retromer complex in aging-related neurodegeneration and diabetes". The Journal of Neuroscience.
(2017). "Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy". European Journal of Human Genetics.
(2016). "A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease". Acta Neuropathologica.
(July 2023). "A familial missense variant in the AD gene ''SORL1'' impairs its maturation and endosomal sorting".
(2023). "The SORL1 p. Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease.".
(2023). ""Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease"". Genetic and Genomic Medicine.
(August 2004). "Loss of apolipoprotein E receptor LR11 in Alzheimer disease". Archives of Neurology.
(December 2005). "Model-guided microarray implicates the retromer complex in Alzheimer's disease". Annals of Neurology.
(September 2005). "Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America.
(January 2023). "Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer". Proceedings of the National Academy of Sciences of the United States of America.
(July 2021). "The Retromer Complex: From Genesis to Revelations". Trends in Biochemical Sciences.
(February 2007). "The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease". Nature Genetics.
(February 2023). "Alzheimer's Disease: An Updated Overview of Its Genetics". International Journal of Molecular Sciences.
(September 2021). "A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease". Nature Genetics.
(2020). "Endosomal recycling reconciles the Alzheimer's disease paradox". Science Translational Medicine.

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