SORL1

Last updated
SORL1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SORL1 , sortilin-related receptor, L(DLR class) A repeats containing, C11orf32, LR11, LRP9, SORLA, SorLA-1, gp250, sortilin related receptor 1
External IDs OMIM: 602005 MGI: 1202296 HomoloGene: 2336 GeneCards: SORL1
Orthologs
SpeciesHumanMouse
Entrez

6653

20660

Ensembl

ENSG00000137642

ENSMUSG00000049313

UniProt

Q92673

O88307

RefSeq (mRNA)

NM_003105

NM_011436
NM_001357261

RefSeq (protein)

NP_003096

NP_035566
NP_001344190

Location (UCSC) Chr 11: 121.45 – 121.63 Mb Chr 9: 41.88 – 42.04 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
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). SORL1 schematic.png
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 Sorl1 ectodomain model and modes of dimerization.png
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. Retromer and SORL1 on tubular endosome.png
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. [5]

Contents

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] .

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]

See also

Related Research Articles

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

Retromer is a complex of proteins that has been shown to be important in recycling transmembrane receptors from endosomes to the trans-Golgi network (TGN) and directly back to the plasma membrane. Mutations in retromer and its associated proteins have been linked to Alzheimer's and Parkinson's diseases.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<span class="mw-page-title-main">Gamma secretase</span>

Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.

<span class="mw-page-title-main">Presenilin</span>

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.

<span class="mw-page-title-main">SNX1</span> Protein-coding gene in the species Homo sapiens

Sorting nexin-1 is a protein that in humans is encoded by the SNX1 gene. The protein encoded by this gene is a sorting nexin. SNX1 is a component of the retromer complex.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

<span class="mw-page-title-main">PSEN2</span> Protein-coding gene in the species Homo sapiens

Presenilin-2 is a protein that is encoded by the PSEN2 gene.

<span class="mw-page-title-main">Sortilin 1</span> Protein-coding gene in the species Homo sapiens

Sortilin (SORT1) is a protein that in humans is encoded by the SORT1 gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitously expressed in many tissues, sortilin is most abundant in the central nervous system. At the cellular level, sortilin functions in protein transport between the Golgi apparatus, endosome, lysosome, and plasma membrane, leading to its involvement in multiple biological processes such as glucose and lipid metabolism as well as neural development and cell death. Moreover, the function and role of sortilin is now emerging in several major human diseases such as hypertension, atherosclerosis, coronary artery disease, Alzheimer’s disease, and cancer. The SORT1 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">UBQLN1</span> Protein-coding gene in the species Homo sapiens

Ubiquilin-1 is a protein that in humans is encoded by the UBQLN1 gene.

<span class="mw-page-title-main">VPS35</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.

<span class="mw-page-title-main">VPS26A</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting-associated protein 26A is a protein that in humans is encoded by the VPS26A gene.

<span class="mw-page-title-main">SNX15</span> Protein-coding gene in the species Homo sapiens

Sorting nexin-15 is a protein that in humans is encoded by the SNX15 gene.

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

<span class="mw-page-title-main">Rudolph E. Tanzi</span> American geneticist

Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, vice-chair of neurology, director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH).

<span class="mw-page-title-main">PLD3</span> Protein-coding gene in the species Homo sapiens

Phospholipase D3, also known as PLD3, is a protein that in humans is encoded by the PLD3 gene. PLD3 belongs to the phospholipase D superfamily because it contains the two HKD motifs common to members of the phospholipase D family, however, it has no known catalytic function similar to PLD1 or PLD2. PLD3 serves as a ssDNA 5' exonuclease in antigen presenting cells. PLD3 is highly expressed in the brain in both humans and mice, and is mainly localized in the endoplasmic reticulum (ER) and the lysosome.

Alison Mary Goate is a professor of neuroscience and Director of the Loeb Center for Alzheimer's Disease at Icahn School of Medicine at Mount Sinai, New York City. She was previously professor of genetics in psychiatry, professor of genetics, and professor of neurology at Washington University School of Medicine.

<span class="mw-page-title-main">LILRA5</span> Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily A member 5 (LILR-A5) also known as CD85 antigen-like family member F (CD85f), immunoglobulin-like transcript 11 (ILT-11), and leukocyte immunoglobulin-like receptor 9 (LIR-9) is a protein that in humans is encoded by the LILRA5 gene. This gene is one of the leukocyte receptor genes that form a gene cluster on the chromosomal region 19q13.4. Four alternatively spliced transcript variants encoding distinct isoforms have been described.

Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), Apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and Clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000137642 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000049313 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: Sortilin-related receptor, L(DLR class) A repeats containing".
  6. ↑ 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. PMID   25669742. S2CID   5166260.
  7. ↑ Szabo MP, Mishra S, Knupp A, Young JE (January 2022). "The role of Alzheimer's disease risk genes in endolysosomal pathways". Neurobiology of Disease. 162: 105576. doi:10.1016/j.nbd.2021.105576. PMC   9071255 . PMID   34871734.
  8. ↑ Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA (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. 157 (1): 277–286. doi:10.1016/S0002-9440(10)64538-5. PMC   1850219 . PMID   10880397.
  9. ↑ Small SA, Simoes-Spassov S, Mayeux R, Petsko GA (October 2017). "Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer's Disease". Trends in Neurosciences. 40 (10): 592–602. doi:10.1016/j.tins.2017.08.003. PMC   5654621 . PMID   28962801.
  10. ↑ Carosi JM, Denton D, Kumar S, Sargeant TJ (2023). "Receptor Recycling by Retromer". Molecular and Cellular Biology. 43 (7): 317–334. doi:10.1080/10985549.2023.2222053. PMC  10348044. PMID   37350516.
  11. 1 2 Simoes S, Guo J, Buitrago L, Qureshi YH, Feng X, Kothiya M, et al. (December 2021). "Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling". Cell Reports. 37 (13): 110182. doi:10.1016/j.celrep.2021.110182. PMC   8792909 . PMID   34965419.
  12. ↑ Lane RF, St George-Hyslop P, Hempstead BL, Small SA, Strittmatter SM, Gandy S (October 2012). "Vps10 family proteins and the retromer complex in aging-related neurodegeneration and diabetes". The Journal of Neuroscience. 32 (41): 14080–14086. doi:10.1523/JNEUROSCI.3359-12.2012. PMC   3576841 . PMID   23055476.
  13. ↑ Holstege, Henne; van der Lee, Sven J.; Hulsman, Marc; Wong, Tsz Hang; van Rooij, Jeroen GJ; Weiss, Marjan; Louwersheimer, Eva; Wolters, Frank J.; Amin, Najaf; Uitterlinden, André G.; Hofman, Albert; Ikram, M. Arfan; van Swieten, John C.; Meijers-Heijboer, Hanne; van der Flier, Wiesje M. (2017). "Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy". European Journal of Human Genetics. 25 (8): 973–981. doi:10.1038/ejhg.2017.87. ISSN   1476-5438. PMC   5567154 . PMID   28537274.
  14. ↑ Verheijen, Jan; Van den Bossche, Tobi; van der Zee, Julie; Engelborghs, Sebastiaan; Sanchez-Valle, Raquel; Lladó, Albert; Graff, Caroline; Thonberg, Håkan; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A.; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Clarimon, Jordi (2016). "A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease". Acta Neuropathologica. 132 (2): 213–224. doi:10.1007/s00401-016-1566-9. ISSN   1432-0533. PMC   4947104 . PMID   27026413.
  15. ↑ Fazeli E, Child DD, Bucks SA, Stovarsky M, Edwards G, Yu CE, et al. (July 2023). "A familial missense variant in the AD gene SORL1 impairs its maturation and endosomal sorting". bioRxiv: 2023.07.01.547348. doi:10.1101/2023.07.01.547348. PMC   10349966 . PMID   37461597.
  16. 1 2 Jensen AM, Raska J, Fojtik P, Monti G, Lunding M, Vochyanova S, et al. (2023). "The SORL1 p. Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease". medRxiv   10.1101/2023.07.09.23292253v1 .
  17. ↑ Holstege, Henne; De Waal, Matthijs W. J.; Tesi, Niccolo; Van Der Lee, Sven J.; ADES-consortium; ADSP consortium; StEP-AD consortium; Knight-ADRC; UCSF/NYGC/UAB (2023). "Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease" (Report). Genetic and Genomic Medicine. doi:10.1101/2023.07.13.23292622.
  18. ↑ 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. PMID   15313836. S2CID   22176694.
  19. ↑ 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. PMID   16315276. S2CID   34144181.
  20. ↑ Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, et al. (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. 102 (38): 13461–13466. Bibcode:2005PNAS..10213461A. doi: 10.1073/pnas.0503689102 . PMC   1224625 . PMID   16174740.
  21. ↑ Jensen AM, Kitago Y, Fazeli E, Vægter CB, Small SA, Petsko GA, Andersen OM (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. 120 (4): e2212180120. Bibcode:2023PNAS..12012180J. doi:10.1073/pnas.2212180120. PMC   9942828 . PMID   36652482.
  22. ↑ Seaman MN (July 2021). "The Retromer Complex: From Genesis to Revelations". Trends in Biochemical Sciences. 46 (7): 608–620. doi:10.1016/j.tibs.2020.12.009. PMID   33526371. S2CID   231753314.
  23. ↑ Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, et al. (February 2007). "The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease". Nature Genetics. 39 (2): 168–177. doi:10.1038/ng1943. PMC   2657343 . PMID   17220890.
  24. ↑ Andrade-Guerrero J, Santiago-Balmaseda A, Jeronimo-Aguilar P, Vargas-Rodríguez I, Cadena-Suárez AR, Sánchez-Garibay C, et al. (February 2023). "Alzheimer's Disease: An Updated Overview of Its Genetics". International Journal of Molecular Sciences. 24 (4): 3754. doi: 10.3390/ijms24043754 . PMC   9966419 . PMID   36835161.
  25. ↑ Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. (September 2021). "A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease". Nature Genetics. 53 (9): 1276–1282. doi:10.1038/s41588-021-00921-z. PMC   10243600 . PMID   34493870.
  26. ↑ Small SA, Petsko GA (2020). "Endosomal recycling reconciles the Alzheimer's disease paradox". Science Translational Medicine. 12 (572): eabb1717. doi:10.1126/scitranslmed.abb1717. PMC   8025181 . PMID   33268506.
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