17 Jan 2025

When teamed up with its partner, the retromer complex, SORL1 carries all manner of precious protein cargo through the endolysosomal system to the cell surface, and back again. With such a busy life, it’s no wonder mutations that hamper SORL1 trafficking cause trouble. In recent years, the sorting receptor has wriggled to center stage of Alzheimer’s pathogenesis, joining the ranks of APP, PS1, and PS2 in what some now call the “causal quartet,” each with variants that invariably lead to AD. In 2023, in collaboration with SORL1 scientists, Alzforum added SORL1 to its mutation database, featuring an interactive diagram mapping some 500 mutations, and their suspected pathogenicities, across the whopping 2,214-amino acid protein (Jul 2023 news). At the time, a handful of small family pedigrees, as well as large exome-sequencing studies, implicated SORL1 as an autosomal-dominant AD gene (Jul 2023 news).

Where does the field stand now, 18 months later? On the genetic front, scientists have published on some of those pathogenic SORL1 variants. These tracked with AD in families, while mechanistic studies revealed that each derailed a different aspect of SORL1 trafficking. SORL1’s sphere of influence now extends beyond European cohorts, with protective variants identified in East Asians. These variants boost SORL1 expression, while risk variants do the opposite, underscoring the importance of SORL1 in fending off AD. On the cell biology front, scientists parsed the role of SORL1 in neurons and microglia, where suppressing the receptor affected endosomal recycling and lysosomal function, respectively. They also found that SORL1 deficiency hampers glucose metabolism in the brain, akin to what happens in the early stages of AD. Finally, preliminary studies hint that a dip in soluble SORL1 in CSF might serve as a biomarker for SORL1 dysfunction. To some, the data place endolysosomal gridlock at the very heart of AD pathogenesis, rather than as a bystander to Aβ and tau aggregation.

Splendor of SORL1. Most of the receptor sits on the outside of the cell membrane or in the lumen of endosomes and lysosomes. Motifs include 10 VPS10p domains (green), two 10CC domains (pink/orange), six YWTD domains (gray), a single EGF domain (orange), 11 CR domains (turquoise), and six 3Fn domains (blue). Its cytoplasmic tail nabs the retromer. [Courtesy of Andersen et al., bioRxiv, 2023.]

Autosomal Dominant?
SORL1’s mobility is vital to its function. After translation, the protein folds within the ER, where its myriad luminal domains arrange themselves to latch onto cargo. Once folded, the protein travels to endosomes, where it dimerizes via its 3Fn-domains (Feb 2023 news). This beckons the retromer complex, which attaches to SORL1 C-terminal tails dangling in the cytoplasm, then whisks the receptor, along with attached cargo, to the cell surface via endosomal tubules. From there, most SORL1 recycles back into endosomes. TNFa converting enzyme (TACE) cleaves about a third, releasing a soluble, “sSORLA” protein into the extracellular space.

It is unsurprising, then, that scientists have found that pathogenic variants tend to impede SORL1 trafficking. Take Y1816C. In a 2023 preprint, researchers led by Olav Andersen of Aarhus University in Denmark reported that this variant tracked with AD in three unrelated families and proposed that the variant causes autosomal-dominant AD (Jul 2023 news on Jensen et al., 2023). That work, published in the Proceedings of the National Academy of Sciences last September, identified where, and how, this variant was marooned in neurons (Jensen et al., 2024).

The scientists found that the Y1816C variant twisted the structure of the third 3Fn domain, thwarting dimerization of SORL1 and rebuffing engagement by the retromer. Most Y1816C SORL1 remained in the endosomes, with scant sSORL1 released from the cell surface.

Another autosomal-dominant SORL1 contender, R953C, gets stranded soon after the protein is made. Scientists led by Jessica Young of the University of Washington reported that this variant, which messes with the structure of SORL1’s YWTD β-propeller domain, also stymies proper folding of the protein, this time in the ER. This puts the kibosh on its travels into the endosome (Fazeli et al., 2024). Due to its sequestration in the ER, R953C, like Y1816C, fails to reach the cell surface, resulting in scant shedding of sSORL1. It also left crucial cargoes, including APP and glutamate receptors, stranded in endosomes.

Y1816C and R953C are the only two variants reported to have family pedigrees hinting at an autosomal-dominant association with AD. However, because genotyping in these families is incomplete or, in the case of Y1816C, at least one known carrier has not yet developed AD, not everyone is convinced. Gaël Nicolas of Normandie University in Rouen, France, thinks the story might be more complex, and that other variants—particularly ApoE4—might contribute to each SORL1 variant’s pathogenicity. For example, all affected carriers of the Y1816C mutation are also ApoE4-positive, while one unaffected carrier is ApoE4-negative, he noted. To his mind, this leaves open the possibility that SORL1 variants by themselves are insufficient to cause AD.

Nicolas' previous work suggests that SORL1 loss-of-function variants only reach complete penetrance among ApoE4 carriers, but he agrees that defects in SORL1 trafficking are likely to tip the balance toward AD (Schramm et al., 2022, Rovelet-Lecrux et al., 2021).

Andersen told Alzforum that in addition to Y1816C and R953C, another variant in an Icelandic family has been identified that appears to track with AD in an autosomal-dominant fashion. None of the family members carry ApoE4, he said. The pedigree and functional studies conducted on this variant have yet to be published.

Even these incomplete and unpublished pedigrees are few and far between. Most of the 500-plus SORL1 variants that have been identified are extremely rare, making pathogenicity difficult to determine. To help, Andersen and colleagues developed bioinformatics and cell-biology approaches. The former looks to variants in structurally related proteins to gauge pathogenicity, while the latter tests the function of variants in specific pathways.

Those related proteins include the low-density lipoprotein receptor (LDLR) and vacuolar protein sorting-10 families. LDLR shares YWTD and CR domains with SORL1, and variants in each cause familial hypercholesterolemia and other disorders. While no known disease-causing variants have been found in VPS10p proteins, the structure of this portion of SORL1 has been solved, helping scientists predict, in silico, how given variants might hobble protein. As Alzforum reported previously, this domain-mapping approach helped the scientists develop a compendium of SORL1 variants, with estimated pathogenicity (Andersen et al., 2023).

Since then, the scientists have honed functional assays to confirm these homology-based approaches. Cell culture and flow cytometry gauge SORL1 maturation, cell surface expression, and sSORL1 shedding. Case in point, they found that SORL1 D1105H, a variant predicted to bungle the folding of the CR1 domain, makes hardly any progress toward the cell surface and barely sheds sSORL1, supporting the idea that this variant is pathogenic (Fazeli et al., 2024). Domain-mapping approaches had suggested as much, and it was identified in one person with AD, but no controls, in an exome sequencing study (Holstege et al., 2023).

Andersen thinks that streamlining these functional assays will further support the pathogenicity predictions for rare variants. He believes sSORL1 in the cerebrospinal fluid might even work as a biomarker for SORL1 dysfunction or deficiency. With Henne Holstege of VU Amsterdam Medical Center, he is testing CSF from carriers of different SORL1 variants. He noted that because levels of SORL1 are also known to dip in people with sporadic AD, more work is needed to determine the normal, and pathological, ranges of sSORL1.

Common Variants, Different Populations
In addition to rare variants that may cause AD, common variants in and around the SORL1 gene that change a person’s risk for AD turned up previously in two genome-wide association studies (Jan 2007 news; Miyashita et al., 2013). In a study published last month in Alzheimer’s and Dementia, scientists led by Nancy Ip of the Hong Kong University of Science and Technology mapped AD risk variants in the SORL1 locus in three East Asian cohorts, including a total of 5,249 people, with or without AD, from mainland China, Hong Kong, and Japan, as well as in a European cohort including 8,588 participants (Zhou et al., 2024). In short, while first author Xiaopu Zhou and colleagues identified protective and risk variants in both the East Asian and in the European cohorts, these variants were distinct in the different populations.

Grouping these East Asian and European variants into blocks, the scientists identified a haplotype that includes the protective alleles of 31 SORL1 variants. Dubbed Hap A, it was far more common among East Asians than Europeans, yet it protected carriers in both populations. Notably, this was significant, regardless of ApoE genotype.

Hap A associated with superior cognitive function, a higher plasma Aβ42/40 ratio, and less plasma p-tau181 in East Asians. This was true even among people with AD, suggesting that in addition to dampening AD risk, the haplotype also stems AD severity and progression. In support of this, among people in the Hong Kong cohort, Hap A weakened the connection between brain Aβ load and cognitive dysfunction. Using plasma proteomics, the authors found reduced levels of pro-inflammatory proteins, and an uptick in neuronal proteins crucial for synaptic function, among Hap A carriers.

Finally, the researchers found that protective variants included within Hap A associated with higher expression of SORL1 in neural tissues; conversely, risk variants were tied to lower expression.

Scott Small of Columbia University in New York commented that Ip’s rigorous genetic analysis complements findings from mechanistic studies, which together drive home the point that SORL1, and by extension, efficient endosomal recycling, protects against AD.

In Microglia, SORL1 Fuels Lysosomes
How does SORL1 defend against AD, or conversely, how does its loss of function beckon the disease? The lion’s share of mechanistic studies to date have focused on the role of SORL1 in neurons, where it most famously shuttles APP. When this falters, APP remains within the endosome, leaving it exposed to BACE1 and thus cranking up production of amyloidogenic Aβ peptides. SORL1 also delivers critical synaptic receptors, such as GLUA1, to the neuronal surface.

Yet, SORL1 gets plenty busy in microglia, as well, albeit on a different set of tasks, namely, supporting the lysosome. Previously, Young and colleagues found that while SORL1-deficient hiPSC-derived neurons were choked with swollen endosomes, human microglial-like cells (hMGLs) had bulging lysosomes instead.

To investigate further, Swati Mishra and colleagues in Young’s lab compared lysosomal function and trafficking in wild-type versus SORL1-knockout hMGLs. A new version of their paper was uploaded to bioRxiv on January 7 (Mishra et al., 2025). Without SORL1, lysosomes floundered because critical proteases, such as cathepsins, failed to reach the organelles. Further experiments implicated a failure in the retromer-dependent retrograde pathway. As opposed to the endosomal recycling pathway, which shuttles proteins between the endosomes and cell surface, the retrograde pathway ferries proteins, including lysosomal enzymes, between the trans-Golgi network and lysosomes. The cation-independent mannose-6-phosphate receptor helps here. CIMPR binds to immature lysosomal enzymes in the TGN and, with the help of the retromer and SORL1, ferries them to the lysosome. SORL1 is responsible for returning CIMPR back to the TGN to pick up more proteases. Without it, the delivery system fails, and critical enzymes miss their ride (image below).

Two Sides of SORLA. In neurons, SORL1 connects to the retromer via VPS26b subunit, and participates in the endosomal recycling pathway (A). In microglia, SORL1 associates with VPS26a, and takes part in the retrograde pathway (B). [Courtesy of Mishra et al., Royal Society Philosophical Transactions B, 2024.]

Deprived of their proteases, these weak microglial lysosomes failed to degrade numerous substrates, including fibrillar Aβ and synaptosomes. The microglia balked at spewing out their contents via lysosomal exocytosis, a process in which lysosomes fuse with the plasma membrane to dump their contents outside of the cell (Apr 2023 conference news). Despite their constipation, SORL1-deficient microglia ramped up phagocytosis when fed with fibrillar Aβ, consuming even more of it than their wild-type counterparts. Increased surface expression of phagocytic receptors TREM2 and P2Y6 may drive this, the authors reported. Still, the SORL1-deficient microglia mounted subpar responses to lipopolysaccharide and other inflammatory triggers.

The findings dovetail with work from Thomas Willnow’s lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin. It found that, in microglia, SORL1 delivers the pattern recognition receptor CD14 to the cell surface, sensitizing the cells to inflammatory stimuli (Ovesen et al., 2024). Together, the findings suggest that  SORL1 deficiency in microglia derails proper trafficking to lysosomes and to the cell surface, while in neurons, the endosomal recycling pathway takes the hit. What explains the specificity? The findings align with the different retromer subunits that interact with SORL1 in neurons versus microglia. Neurons mostly produce VPS26b subunit, which travels the endosomal recycling pathway, while microglia make the VPS26a subunit, which is most active in the retrograde pathway.

“Taken together, SORL1-retromer dysfunction in the endolysosomal network can explain two early and significant events in AD: neurodegeneration and neuroinflammation,” wrote Mishra and Young in an opinion paper discussing the roles of SORL1 in neurons and microglia (Mishra et al., 2024).

The primacy of endolysosomal dysfunction in neurons and microglia aligns with a recent report that, in AD, both ApoE and Aβ aggregate within the microglial lysosome, compromising its function (Oct 2024 news). The authors of that study, led by Mikael Simons of the German Center for Neurodegenerative Diseases in Munich, proposed that these festering lysosomal aggregates could later seed extracellular plaques, when microglia either spew them out or die. Similar ideas about the intracellular origins of Aβ plaques have been proposed for neurons (Jun 2022 news).

How might SORL1 fit into this emerging picture? “I think SORL1 deficiency induces a double whammy,” Small wrote to Alzforum. “It first triggers neurons to have endosomal dysfunction, which leads to Aβ secretion and synaptic dysfunction. At the same time microglia can’t respond normally to this early nondegenerative process, which accelerates it.” All of this remains to be tested, he added.

For her part, Young will use hiPSC co-culture models to assess how different SORL1 variants, starting with R953C, impact the endolysosomal network in neurons and microglia. She told Alzforum that it’s possible some variants wreak more havoc in one cell type than another, based on how they influence trafficking.

Besides synaptic dysfunction, neuroinflammation, and Aβ accumulation, other consequences of SORL1 loss are under investigation. For example, SORL1 was recently found to bind tau and, when mutated, promote its intracellular seeding and aggregation (May 2024 news). Studies in mini-pigs, mice, and rats suggest that SORL1 deficiency spells metabolic troubles in the brain, akin to those that crop up early in AD (Bøgh et al., 2024; Wang et al., 2024). Andersen, who co-led one of these studies, told Alzforum that given SORL1’s pivotal role in the endolysosomal system, its loss could influence metabolism in myriad ways, such as putting a wrench in insulin receptor trafficking. It’s early days in terms of understanding how SORL1 loss contributes to waning glucose metabolism, as well as many of the other characteristic features of AD, he said.—Jessica Shugart

Comments

1. • Gregory Petsko
     Harvard Medical School and Brigham&Women's Hospital
   • Posted: 23 Jan 2025

   Another outstanding piece of reporting, Jessica Shugart. Congratulations and thanks for keeping us so well-informed.

   View all comments by Gregory Petsko

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References

Mutation Interactive Images Citations

1. SORL1 18 Jul 2023

News Citations

1. Sorting Out SORL1: 500+ Mutations Mapped, Prioritized in Alzforum Dataset 18 Jul 2023
2. When Missense Variants Derail SORL1 Traffic, Destination Is Dementia 18 Jul 2023
3. When SORL1 Dimerizes in Endosomes, Retromers Recycle APP Faster 1 Feb 2023
4. SORLA Soars—Large Study Links Gene to Late-onset AD 15 Jan 2007
5. From Phagocytosis to Exophagy: Microglia's Digestive Tract Dissected 25 Apr 2023
6. A Match Made in Microglia? ApoE and Aβ Click in Lysosomes, Seeding Plaque 30 Oct 2024
7. Behold PANTHOS, a Toxic Wreath of Perinuclear Aβ That Kills Neurons 5 Jun 2022
8. Might SORL1 Bind Tau in Glia, Fuel Its Aggregation? 4 May 2024

Mutations Citations

1. SORL1 Y1816C
2. SORL1 R953C

Paper Citations

1. Jensen AM, Raska J, Fojtik P, Monti G, Lunding M, Vochyanova S, Pospisilova V, vanderLee SJ, VanDongen J, Bossaerts L, VanBroeckhoven C, Dols O, Lleo A, Benussi L, Ghidoni R, Hulsman M, Sleegers K, Bohaciakova D, Holstege H, Andersen O. The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease. 2023 Jul 13 10.1101/2023.07.09.23292253 (version 1) medRxiv.
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Further Reading

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