Jensen AM, Kitago Y, Fazeli E, Vægter CB, Small SA, Petsko GA, Andersen OM. Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer. Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2212180120. Epub 2023 Jan 18 PubMed.

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  1. The sortilin-related receptor (SORL1) is a large neuronal protein significantly implicated in the pathogenesis of Alzheimer’s disease. One of its well-studied roles is to transport the amyloid precursor protein (APP) through cellular compartments called endosomes, and when this is disrupted, cells produce increased levels of the toxic, APP-derived peptide Aβ. This study by Jensen and colleagues provides new and important information about how SORL1 can form dimeric structures important for recruiting APP into membrane tubules for endosomal transport. This occurs through another endosomal protein complex linked to Alzheimer’s called retromer. These new insights could pave the way for designing either molecular or genetic tools that target these pathogenic pathways in Alzheimer’s disease.

    View all comments by Brett Collins

  2. SORLA is an integral membrane protein linked to early and late-onset AD. In this study, Jensen and colleagues used a variety of approaches, including GFP nanotraps, bimolecular fluorescence complementation assays, and molecular modelling of the SORLA structure, to define how the VPS10P domain and the fibronectin-type III repeats within the ectodomain drive SORLA dimerization.

    As an integral membrane protein, SORLA undergoes sorting and transport through the endosomal network. Here, it is orientated such that its ectodomain is facing into the endosomal lumen and its short carboxy terminal “tail” is exposed to the cytoplasm. The authors propose that SORLA dimerization serves to influence the assembly of the retromer coat on the cytoplasmic facing endosomal leaflet to facilitate the retromer-mediated sorting of SORLA and its associated protein APP through the endosomal network. Indeed, they go one step further to show that disruption of SORLA dimerization leads to an increase in amyloidogenic processing of APP, thereby linking the observations back to AD.

    With perturbed retromer function already closely associated with onset of AD, this thought-provoking study will be of significant interest to the AD community and, more broadly, those interested in the field of retromer biology and endosomal cargo sorting.

    View all comments by Peter Cullen

  3. The VPS10 family of receptors is comprised of sortilin, SorL1, SorCS1, SorCS2, and SorCS3, and each of these plays one or more roles in the sorting and processing of integral membrane proteins as they move through the central vacuolar pathway. Many of these molecules have also been implicated in the pathogenesis of major neurodegenerative disorders. SorL1 (SorLA) is associated with Alzheimer’s disease (AD), while sortilin is associated with frontotemporal lobar degeneration (FTLD). SorL1 was first identified as a receptor for apolipoprotein E, and the implication that SorL1 played a role in AD was established by the identification of variants that segregated with AD in genome-wide association studies (Rogaeva et al., 2007). These VPS10 family members also interact with the VPS35 component of the retromer, a molecule also implicated in the pathogenesis of AD by Small et al. (2005). The underlying mechanism of action of VPS10 proteins is to control the partitioning of transmembrane cargoes between the trans Golgi network (TGN) and the endosomal system. The Alzheimer’s amyloid precursor protein (APP) is one such transmembrane protein cargo for transport by SorL1 and the VPS35 retromer. However, what has been missing until now is the molecular mechanism underlying how SorL1 and VPS35 interact.

    This new paper by Jensen et al. promises to change that. Using a SorL1 fragment that includes the fibronectin-type-III, transmembrane, and cytoplasmic domains (a fragment known as the SorL1 mini-receptor), these authors demonstrate directly that these domains of SorL1 can dimerize, and that this is the key event in enhancing Vps35-retromer-dependent sorting of APP, including specification of the residence time of APP in the amyloidogenic pathway. In intact cells, SorL1 dimers, such as those generated by Jensen and colleagues, are selectively localized in the endosomal compartment, while monomers tend to be more abundant in the TGN.

    Several groups had previously demonstrated that the overexpression of full-length SorL1 decreased APP trafficking in the secretory pathway, while also assisting APP in recycling out of the endosome. To investigate the consequences of SorL1 dimerization, Jensen et al. transfected N2a cells with various combinations of human APP, together with SorL1, in the absence or presence of the SorL1 mini-receptor. In line with previous results, SorL1 alone decreased both amyloidogenic and non-amyloidogenic processing. However, when both SorL1 and the mini-receptor were present, Jensen observed decreased processing of APP through both pathways, with a surprising elevation in the level of the non-amyloidogenic APP carboxyl-terminal fragment. They concluded that this combination represented a phenocopy of the retromer stabilization that some of these same investigators had induced with small molecules in a previous study (Mecozzi et al., 2014). 

    To visualize how these phenomena were occurring at the molecular level, Jensen turned to the available crystal structure of the SorL1 VPS10 and found that several alternative structures were predicted: one model held that local dimers could be held together by the fibronectin-type-III domain or the Vps10 domain (or both), while the other model predicted that dimerization sites from different molecules led to formation of a large polymer of SorL1 molecules that coat endosomal tubules. To determine which of these models was more likely, Jensen turned to the AlphaFold protein folding prediction platform. The original modeling of SorL1 structure turned out to be flawed, so AlphaFold was applied selectively to the SorL1 ectodomain. In the newer iteration of AlphaFold, Jensen determined that the more likely model was the latter (i.e., the one that predicted polymerization of SorL1 and the retromer on endosomal tubules).

    These results have multiple therapeutic implications. In addition to the chemical retromer stabilizers that this group has reported, it is now possible to consider an alternative strategy in which gene therapy might be used to deliver the SorL1 mini-receptor to the brains of AD patients. This would expand the list of potential AD gene therapy strategies beyond the current use of adenoviral-associated viruses to deliver APOE ε2 DNA to treat symptomatic APOE ε4 homozygotes (Kaplitt et al., 2022). 

    References:

    Kaplitt M, Leopold P, Noch E, Ivanidze J, Chazen L, Crystal R, Kaminsky S, Bowe H, Wang M, Ballon D, Dyke J, Sondhi D, Gandy S, Giannantoni-Ibelli G, Barth JA. A Phase 1, Open-Label, 52-Week, Multicenter Study to Evaluate the Safety and Biochemical Efficacy of AAV Gene Therapy (LX1001) in Patients with APOE4 Homozygote Alzheimer’s Disease. Interim Data. JPAD 2022; 9(1): S33. JPAD CTAD Abstracts

    Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA, Ringe D, Small SA. Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol. 2014 Jun;10(6):443-9. Epub 2014 Apr 20 PubMed.

    Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.

    Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, Honig L, Vonsattel JP, Kim TW. Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann Neurol. 2005 Dec;58(6):909-19. PubMed.

    View all comments by Sam Gandy

  4. Endosomal dysfunction is a consistent and early cellular phenotype in AD. The gene SORL1 codes for an endosomal receptor (SORLA) that is strongly associated with increased AD risk. In this study, Jensen and colleagues further elucidate the functional interactions of SORL1 with the multi-protein sorting complex retromer. Using elegant biochemical studies and structural analysis, the group shows how SORLA, a very large protein, can fold to fit into an endosomal tubule. Furthermore, they identify key domains that can dimerize and stabilize retromer, thereby enhancing retromer-related endosomal recycling of APP. This has a beneficial effect of reducing amyloidogenic cleavage by APP. This work is reminiscent of retromer chaperones, small molecules that stabilize the cargo-recognition core of retromer and enhance its function, in particular reducing APP cleavage and tau phosphorylation (Mecozzi et al., 2014; Young et al., 2018). 

    Here, for the first time, the authors identify the distinct domains of SORL1 that can dimerize and promote stabilization of the SORL1-retromer complex—the 3Fn domains and the VPS10 domains. As each of these has been shown to harbor pathogenic variants in SORL1, this is strongly suggestive that these variants may cause AD by disrupting endosomal recycling.  The endosomal system is highly complex and thinking how to design therapeutic options for this pathway is challenging. However, this work paves the way for new targets for AD that focus on the SORL1-retromer interaction as a tractable unit of the overall pathway for therapeutic design. Important future studies should focus on how this unit works to recycle other proteins that that are implicated in AD-related neurodegeneration, including glutamate receptors and neurotrophin receptors, both of which are essential for neuronal health and function.

    References:

    Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA, Ringe D, Small SA. Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol. 2014 Jun;10(6):443-9. Epub 2014 Apr 20 PubMed.

    Young JE, Fong LK, Frankowski H, Petsko GA, Small SA, Goldstein LS. Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. Stem Cell Reports. 2018 Mar 13;10(3):1046-1058. Epub 2018 Mar 1 PubMed.

    View all comments by Jessica Young

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This paper appears in the following:

News

  1. When SORL1 Dimerizes in Endosomes, Retromers Recycle APP Faster
  2. When Missense Variants Derail SORL1 Traffic, Destination Is Dementia

Mutations

  1. SORL1 W1563C
  2. SORL1 R1593S
  3. SORL1 L1617V
  4. SORL1 P1619Q
  5. SORL1 P1654S
  6. SORL1 P1654L
  7. SORL1 L1661F
  8. SORL1 I1669T
  9. SORL1 G1681D
  10. SORL1 W1698C
  11. SORL1 I1710T
  12. SORL1 V1721I
  13. SORL1 G1732A
  14. SORL1 I1753V
  15. SORL1 I1755T
  16. SORL1 I1755M
  17. SORL1 F1765C
  18. SORL1 Y1816C
  19. SORL1 P1844S
  20. SORL1 A1850T
  21. SORL1 V1858A
  22. SORL1 W1862C
  23. SORL1 V1909I
  24. SORL1 R1910H
  25. SORL1 P1955L
  26. SORL1 V1967I (I1967V)
  27. SORL1 L1993F
  28. SORL1 I2004L
  29. SORL1 Y2059C
  30. SORL1 V2097I
  31. SORL1 A2099G