SORL1

{{Short description|Protein-coding gene in the species Homo sapiens}}

{{Infobox_gene}}

File:SORL1 schematic.png

File:Sorl1 ectodomain model and modes of dimerization.png

File:Retromer and SORL1 on tubular endosome.png

Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene.{{cite web | title = Entrez Gene: Sortilin-related receptor, L(DLR class) A repeats containing | url = https://www.ncbi.nlm.nih.gov/gene/6653}}

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;{{cite journal | vauthors = Small SA, Petsko GA | title = Retromer in Alzheimer disease, Parkinson disease and other neurological disorders | journal = Nature Reviews. Neuroscience | volume = 16 | issue = 3 | pages = 126–132 | date = March 2015 | pmid = 25669742 | doi = 10.1038/nrn3896 | s2cid = 5166260 }} the gene is predominantly expressed in the central nervous system.{{cite journal | vauthors = Szabo MP, Mishra S, Knupp A, Young JE | title = The role of Alzheimer's disease risk genes in endolysosomal pathways | journal = Neurobiology of Disease | volume = 162 | pages = 105576 | date = January 2022 | pmid = 34871734 | pmc = 9071255 | doi = 10.1016/j.nbd.2021.105576 }} Endosomal traffic jams linked to SORL1 retromer dysfunction are the earliest cellular pathology in both familial and the more common sporadic Alzheimer’s patients.{{cite journal | vauthors = Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA | title = Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations | journal = The American Journal of Pathology | volume = 157 | issue = 1 | pages = 277–286 | date = July 2000 | doi = 10.1016/S0002-9440(10)64538-5 | pmid = 10880397 | pmc = 1850219 }}{{cite journal | vauthors = Small SA, Simoes-Spassov S, Mayeux R, Petsko GA | title = Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer's Disease | journal = Trends in Neurosciences | volume = 40 | issue = 10 | pages = 592–602 | date = October 2017 | pmid = 28962801 | pmc = 5654621 | doi = 10.1016/j.tins.2017.08.003 }}

Retromer regulates protein trafficking from the early endosome either back to the trans-Golgi (retrograde) or back to the plasma membrane (direct recycling).{{cite journal | vauthors = Carosi JM, Denton D, Kumar S, Sargeant TJ | title = Receptor Recycling by Retromer | journal = Molecular and Cellular Biology | volume = 43 | issue = 7 | pages = 317–334 | date = 2023 | pmid = 37350516 | pmc = 10348044 | doi = 10.1080/10985549.2023.2222053 }} Two forms of retromer are known: the VPS26A retromer and the VPS26B retromer, the latter being dedicated to direct recycling in the CNS.{{cite journal | vauthors = Simoes S, Guo J, Buitrago L, Qureshi YH, Feng X, Kothiya M, Cortes E, Patel V, Kannan S, Kim YH, Chang KT, Hussaini SA, Moreno H, Di Paolo G, Andersen OM, Small SA | display-authors = 6 | title = Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling | journal = Cell Reports | volume = 37 | issue = 13 | pages = 110182 | date = December 2021 | pmid = 34965419 | pmc = 8792909 | doi = 10.1016/j.celrep.2021.110182 }} 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.{{cite journal | vauthors = Lane RF, St George-Hyslop P, Hempstead BL, Small SA, Strittmatter SM, Gandy S | title = Vps10 family proteins and the retromer complex in aging-related neurodegeneration and diabetes | journal = The Journal of Neuroscience | volume = 32 | issue = 41 | pages = 14080–14086 | date = October 2012 | pmid = 23055476 | pmc = 3576841 | doi = 10.1523/JNEUROSCI.3359-12.2012 }}

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,{{Cite journal |last1=Holstege |first1=Henne |last2=van der Lee |first2=Sven J. |last3=Hulsman |first3=Marc |last4=Wong |first4=Tsz Hang |last5=van Rooij |first5=Jeroen GJ |last6=Weiss |first6=Marjan |last7=Louwersheimer |first7=Eva |last8=Wolters |first8=Frank J. |last9=Amin |first9=Najaf |last10=Uitterlinden |first10=André G. |last11=Hofman |first11=Albert |last12=Ikram |first12=M. Arfan |last13=van Swieten |first13=John C. |last14=Meijers-Heijboer |first14=Hanne |last15=van der Flier |first15=Wiesje M. |date=2017 |title=Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy |journal=European Journal of Human Genetics |language=en |volume=25 |issue=8 |pages=973–981 |doi=10.1038/ejhg.2017.87 |pmid=28537274 |issn=1476-5438|pmc=5567154 }} indicating that SORL1 is haploinsufficient.{{Cite journal |last1=Verheijen |first1=Jan |last2=Van den Bossche |first2=Tobi |last3=van der Zee |first3=Julie |last4=Engelborghs |first4=Sebastiaan |last5=Sanchez-Valle |first5=Raquel |last6=Lladó |first6=Albert |last7=Graff |first7=Caroline |last8=Thonberg |first8=Håkan |last9=Pastor |first9=Pau |last10=Ortega-Cubero |first10=Sara |last11=Pastor |first11=Maria A. |last12=Benussi |first12=Luisa |last13=Ghidoni |first13=Roberta |last14=Binetti |first14=Giuliano |last15=Clarimon |first15=Jordi |date=2016 |title=A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease |journal=Acta Neuropathologica |volume=132 |issue=2 |pages=213–224 |doi=10.1007/s00401-016-1566-9 |issn=1432-0533 |pmc=4947104 |pmid=27026413}} 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.{{cite journal | vauthors = Fazeli E, Child DD, Bucks SA, Stovarsky M, Edwards G, Yu CE, Latimer C, Kitago Y, Bird T, Andersen OM, Jayadev S, Young JE | display-authors = 6 | title = A familial missense variant in the AD gene SORL1 impairs its maturation and endosomal sorting | journal = bioRxiv | pages = 2023.07.01.547348 | date = July 2023 | pmid = 37461597 | pmc = 10349966 | doi = 10.1101/2023.07.01.547348 }}{{Cite medRxiv |vauthors=Jensen AM, Raska J, Fojtik P, Monti G, Lunding M, Vochyanova S, Pospisilova V, van der Lee SJ, Van Dongen J, Bossaerts L, Van Broeckhoven C |display-authors=6 |title=The SORL1 p. Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease. |date=2023 |medrxiv=10.1101/2023.07.09.23292253v1}} In fact, specific missense variants have been observed only in AD cases, some of which may have a dominant negative effect.{{Cite report |url=http://medrxiv.org/lookup/doi/10.1101/2023.07.13.23292622 |title="Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease" |last1=Holstege |first1=Henne |last2=De Waal |first2=Matthijs W. J. |date=2023 |publisher=Genetic and Genomic Medicine |doi=10.1101/2023.07.13.23292622 |language=en |last3=Tesi |first3=Niccolo |last4=Van Der Lee |first4=Sven J. |last5=ADES-consortium |last6=ADSP consortium |last7=StEP-AD consortium |last8=Knight-ADRC |last9=UCSF/NYGC/UAB|doi-access=free }}[https://www.alzforum.org/news/research-news/when-missense-variants-derail-sorl1-traffic-destination-dementia .][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