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Cited by 38Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCellular transport and secretion

The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index; 29 of the 48 sources its claims cite were checked for support.

Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

Open access
Rovelet-Lecrux, Anne, Feuillette, Sebastien, Miguel, Laetitia, Schramm, Catherine, Pernet, Ségolène, Quenez, Olivier, Ségalas-Milazzo, Isabelle, Guilhaudis, Laure, Rousseau, Stéphane, Riou, Gaëtan, Frébourg, Thierry, Campion, Dominique, Nicolas, Gaël, Lecourtois, Magalie·2021·Acta Neuropathologica Communications
DOI 10.1186/s40478-021-01294-4PMC PMC8684260

Published version of a preprint

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Abstract

The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This study identifies impaired SorLA maturation and trafficking as a new loss-of-function mechanism for rare SORL1 missense variants in Alzheimer disease. A subset of variants is retained in the endoplasmic reticulum, reducing mature SorLA at the plasma membrane and endosomes, with two variants increasing Aβ secretion in hiPSCs.

Key findings

  • Of 70 rare SORL1 missense variants overexpressed in HEK293 cells, 15 (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) showed a maturation/trafficking-deficient phenotype; this was 15/48 Mis3 variants (~30%).
  • In CRISPR/Cas9-modified hiPSCs expressing variants at endogenous levels, R332W, S577P, and R654W showed maturation defects, with a gradual effect S577P < R332W < R654W; R332W and R654W also had significantly lower mature SorLA at the plasma membrane.
  • The maturation-defective variants were largely retained in the endoplasmic reticulum and showed reduced early endosome localization; R332W and R654W increased Aβ40 secretion (121.4 ± 14.4%, p < 0.01 and 127.2 ± 19.6%, p < 0.001, respectively), while S124R, N371T, and S577P did not (100.4 ± 8.9, 99.1 ± 11.0, and 94.7 ± 12.6).
  • Structural analysis suggested impaired trafficking could result from subtle 3D-structure changes and altered interatomic interactions, rather than major global destabilization.

Methods

  • Rare SORL1 missense variants were selected from 1,383 exomes of unrelated AD probands (EOAD in 97%), using allele frequency <1% in gnomAD non-neuro and Mis0–Mis3 classification by PolyPhen-2, SIFT, and MutationTaster; 70 variants were studied.
  • HEK293 cells were used for transient overexpression, Western blotting, glycosidase treatments, secretion assays with truncated SorLA759/SorLA2131 constructs, and cell-surface biotinylation.
  • Five variants (S124R, R332W, N371T, S577P, R654W) were introduced into hiPSCs by CRISPR/Cas9 and studied at endogenous levels by Western blotting, biotinylation, immunofluorescence/colocalization, and Aβ40 MSD assays; structural effects were modeled with DynaMut on the Vps10p domain (PDB ID 3WSY).

Limitations

  • The authors state that HEK293 overexpression may exacerbate variant effects and overload ER quality control, and that hiPSC lines carried mutations at the homozygous state whereas patients carry SORL1 missense variants at the heterozygous state.
  • The authors note that short-term hiPSC cultures cannot exclude long-term, aging-related, or cell-specific effects, particularly for S577P, which showed no Aβ secretion increase; structural analysis was limited to the Vps10p domain because that crystal structure was available.
  • Evident from the text: only 5 of 70 variants were validated in hiPSCs, and some effects did not reach statistical significance after Bonferroni correction (e.g., S577P plasma membrane levels; R729W secretion).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s40478-021-01294-4

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

29 of 48 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The penetrance of SORL1 protein-truncating variants appears to be incomplete.

    “However, the penetrance of such variants appears to be incomplete, so that they should still be considered with caution in a clinical setting [25].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Schramm C, Charbonnier C, Zaréa A, Lacour M, Wallon D, CNRMAJ collaborators, et al (2021) Penetrance estimation of SORL1 loss-of-function variants using a family-based strategy adjusted on APOE genotypes suggest a non-monogenic inheritance. bioRxiv. 2021.06.30.450554 source
  • Interpretationreasoning

    The presence of both immature and mature species at the plasma membrane in HEK293 cells could be related to overexpression of SorLA and saturation of the ER quality control system.

    “The presence of both species at the plasma membrane in HEK293 cells, which is consistent with the data previously reported by other groups [3, 9], could therefore be related to the overexpression of SorLA and the saturation of the ER quality control system.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Jacobsen L, Madsen P, Jacobsen C, Nielsen MS, Gliemann J, Petersen CM (2001) Activation and functional characterization of the mosaic receptor SorLA/LR11. J Biol Chem 276:22788–22796 source

      The cell-surface localization results (Fig. 8, page unavailable) show a double band for SorLA, including in the surface-biotinylated fraction, and identify differential glycosylation. This is consistent with two surface species, but the experiments used CHO cells, not HEK293 cells, and do not identify the bands as immature and mature. The proposed ER-quality-control explanation is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [9] Christensen SK, Narimatsu Y, Simoes S, Goth CK, Vægter CB, Small SA, et al. Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer’s-associated protein sorLA. bioRxiv. 2020;2020.07.12.199885. source
  • Premisecitation

    To date, only 6 SORL1 missense variants have been studied in vitro and have shown varying degrees of decrease in SorLA protein function.

    “To date, only 6 missense variants have been studied in vitro and have shown varying degrees of decrease in SorLA protein function [21, 28, 29].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [21] Caglayan S, Takagi-Niidome S, Liao F, Carlo A-S, Schmidt V, Burgert T, et al (2014) Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation. Sci Transl Med 6:223ra20 source
    • cites [28] Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M et al (2015) Coding mutations in SORL1 and Alzheimer disease. Ann Neurol 77:215–227 source

      The Results describe in vitro functional tests of three SORL1 missense variants—E270K, A528T, and T947M—and report differing effects on APP processing and interaction with SORL1. The paper does not establish that only six variants had been studied in vitro to date; that total may draw on the sentence’s other citations. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [29] Cuccaro ML, Carney RM, Zhang Y, Bohm C, Kunkle BW, Vardarajan BN et al (2016) SORL1 mutations in early- and late-onset Alzheimer disease. Neurol Genet 2:e116 source

      The Results sections report in vitro functional effects for two SORL1 missense variants, T588I and T2134M, and say that two others, A528T and T947M, were assessed previously. The paper does not establish that only six variants had been studied in vitro to date, so it supports the functional-effects portion but not the stated total. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingcitation

    Removal of all N-linked glycans by PNGase F resulted in a single band migrating at ~250 kDa, corresponding to the predicted molecular weight of full-length SorLA.

    “As previously shown [3, 9], removal of all N-linked glycans by treatment with PNGase F resulted in a single band that migrates at ~ 250 kDa, which corresponds to the predicted molecular weight of the full-length SorLA (SorLAFL) protein (Fig. 2a).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Jacobsen L, Madsen P, Jacobsen C, Nielsen MS, Gliemann J, Petersen CM (2001) Activation and functional characterization of the mosaic receptor SorLA/LR11. J Biol Chem 276:22788–22796 source

      In the SorLA localization results (Fig. 8D; page unavailable), the paper reports that PNGase-F deglycosylation of SorLA from transfected cells produced a single band. Our copy does not state that the band migrated at approximately 250 kDa or that this matched the predicted molecular weight of full-length SorLA. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [9] Christensen SK, Narimatsu Y, Simoes S, Goth CK, Vægter CB, Small SA, et al. Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer’s-associated protein sorLA. bioRxiv. 2020;2020.07.12.199885. source

      In “Characterization of the mature and immature forms of sorLA” (Fig. 2A; page unavailable), the paper reports that PNGase F collapsed two bands from cells expressing full-length sorLA into one faster-migrating band. The text does not specify that the resulting band migrated at approximately 250 kDa or identify that value as the predicted molecular weight of full-length sorLA. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Loss of SORL1 expression in several mouse models of AD increases extracellular Aβ levels.

    “Indeed, loss of SORL1 expression in several mouse models of AD increases extracellular Aβ levels, the aggregation of which triggers AD pathology [15–17].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [15] Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 102:13461–13466 source

      The Results report about 30% higher Aβ levels in cortical brain extracts from sorLA-deficient mice than in controls. They do not establish that the increase was extracellular or demonstrate it in several AD mouse models; the paper describes a sorLA-deficient mouse model and reports no amyloid plaque deposition in it. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [16] Dodson SE, Andersen OM, Karmali V, Fritz JJ, Cheng D, Peng J et al (2008) Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer’s disease. J Neurosci 28:12877–12886 source

      The Results report increased brain Aβ levels and amyloid plaque deposition after LR11/SORL1 loss in PS1/APP mice, particularly at early ages. But this paper directly tests one AD mouse model, not several, and measures Aβ in brain extracts and plaques rather than specifically measuring extracellular Aβ levels. The Discussion mentions a separate PDAPP study, but that does not make it a second model tested here. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [17] Rohe M, Carlo A-S, Breyhan H, Sporbert A, Militz D, Schmidt V et al (2008) Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. J Biol Chem 283:14826–14834 source

      The Results report increased Aβ production and a threefold higher plaque burden when SORLA was lost in PDAPP mice; a second SORLA-deficient line on the PDAPP background also showed increased plaques. The paper does not establish increased extracellular Aβ levels across several distinct AD mouse models: its AD experiments use the PDAPP model, and its Aβ measurements are not specified as extracellular. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Probably not a substantial claim. 29
  • It may state two separate claims as one. 41
  • The quote only partly states this claim. 1

  • Probably not a substantial claim.

    Premisecitation

    The transport of misfolded glycoproteins in the ER is inhibited by a process called quality control.

    “The transport of misfolded glycoproteins in the ER is inhibited by a process called quality control [46].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [46] Adams BM, Oster ME, Hebert DN (2019) Protein quality control in the endoplasmic reticulum. Protein J 38:317–329 source

  • It may state two separate claims as one.

    Premisecitation

    Overexpression of SORL1 in neuronal and non-neuronal cell lines limits APP processing and decreases Aβ production.

    “On the other hand, overexpression of SORL1 in neuronal and non-neuronal cell lines limits the processing of APP, the Aβ precursor protein, and decreases Aβ production [5, 15, 18, 19].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [5] Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen OM et al (2007) SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem 282:32956–32964 source
    • cites [15] Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 102:13461–13466 source

      The Results report that sorLA overexpression in neuronal SH-SY5Y cells reduced APP processing products, including Aβ (Fig. 4D). The Results also show altered APP trafficking in non-neuronal CHO cells, but do not report reduced APP processing or Aβ production in those cells. Thus, the claimed effect across both types of cell line is not fully supported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [18] Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI et al (2006) The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci 26:1596–1603 source

      The Results report that LR11 (SORL1) overexpression in HEK293 cells reduced full-length APP and extracellular Aβ, while the Discussion attributes the Aβ reduction to altered APP processing. The copy does not show these effects in an overexpressing neuronal cell line, and it reports increased APP fragments rather than an overall limit on APP processing. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [19] Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177 source

      The Results report that SORL1 overexpression decreased Aβ production to 82% of the control value and describe a mechanism in which SORL1 diverts APP away from pathways where it is cleaved. The Methods identify a non-neuronal HEK293 cell line, but our copy does not report the overexpression result in a neuronal cell line. No page numbers are available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    SorLA deficiency results in increased production of Aβ peptides and thus a higher risk of AD.

    “Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD.”
    • Also stated in: § Introduction · plain
      “Indeed, loss of SORL1 expression in several mouse models of AD increases extracellular Aβ levels, the aggregation of which triggers AD pathology [15–17].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [15] Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 102:13461–13466 source

      The Results report approximately 30% higher brain Aβ levels in sorLA-deficient mice. The Discussion says altered sorLA activity may be a risk factor for AD, but the paper does not establish that deficiency results in higher AD risk. Page numbers are not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [16] Dodson SE, Andersen OM, Karmali V, Fritz JJ, Cheng D, Peng J et al (2008) Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer’s disease. J Neurosci 28:12877–12886 source

      The Introduction reports that LR11/SORLA deficiency increased Aβ40 and Aβ42 in an AD mouse model. The Discussion treats increased human AD susceptibility as a possibility supported by genetic associations, not an established consequence of SorLA deficiency; the claim states that risk as fact. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [17] Rohe M, Carlo A-S, Breyhan H, Sporbert A, Militz D, Schmidt V et al (2008) Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. J Biol Chem 283:14826–14834 source

      The Results report increased Aβ40 in SORLA-deficient mice, and the Discussion reports increased amyloid peptide formation across mouse models. The Discussion says these findings support the possibility that insufficient SORLA expression may be a risk factor for human AD; it does not establish that deficiency results in a higher risk in people. Page numbers were not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Newly synthesized SorLA molecules follow the constitutive secretory pathway from the ER to the cell surface through the Golgi, and undergo post-translational modifications and maturation, resulting in immature and mature species.

    “Newly synthesized SorLA molecules follow the constitutive secretory pathway from the endoplasmic reticulum (ER) to the cell surface, through the Golgi. During their transport through the secretory pathway, SorLA proteins are subjected to several post-translational modifications, including both N- and O-glycosylation, and maturation processes [3–9], resulting in the presence of immature and mature”
    Quote in the paperSubstantial claim5 of 7 sources checked
    • cites [3] Jacobsen L, Madsen P, Jacobsen C, Nielsen MS, Gliemann J, Petersen CM (2001) Activation and functional characterization of the mosaic receptor SorLA/LR11. J Biol Chem 276:22788–22796 source

      The Discussion states that SorLA is synthesized as an inactive proreceptor and matures through propeptide cleavage in the late Golgi/TGN. The results also show differential glycosylation and about 10% of full-length SorLA at the cell surface. Our copy does not establish O-glycosylation or describe a constitutive ER-to-surface route for newly synthesized SorLA. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [4] Fiete D, Mi Y, Oats EL, Beranek MC, Baenziger JU (2007) N-Linked oligosaccharides on the low density lipoprotein receptor homolog SorLA/LR11 are modified with terminal GalNAc-4-SO4 in kidney and brain*. J Biol Chem 282:1873–1881 source

      The Abstract (page unavailable) describes SorLA/LR11 as shuttling among the plasma membrane, endosomes, and Golgi, and reports a modification of its N-linked oligosaccharides. It does not establish constitutive transport from the ER to the surface, O-glycosylation, or the formation of immature and mature species; searches for those terms found no supporting passage. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [5] Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen OM et al (2007) SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem 282:32956–32964 source

      The Results (page not supplied) place SorLA in ER and Golgi fractions and detect a small amount of wild-type SorLA at the cell surface. But the paper says SorLA’s exact trafficking route had not been established. Its Results describe N- and O-glycosylation and immature and mature species of APP, not SorLA, so those parts of the claim are unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [6] Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, Wu C et al (2012) Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci 32:1467–1480 source

      The Discussion describes SorLA moving through the secretory pathway to the cell surface. The section ‘Reduced expression of sorLA-FANSHY36A at the cell surface’ reports maturation through acquisition of glycosylation, and the Figure 4 legend labels immature and mature species. Our copy does not specify both N- and O-glycosylation or explicitly trace the initial route from the ER through the Golgi. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [7] Steentoft C, Vakhrushev SY, Joshi HJ, Kong Y, Vester-Christensen MB, Schjoldager KT-BG et al (2013) Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology. EMBO J 32:1478–1488 source
    • cites [8] Hampe W, Riedel IB, Lintzel J, Bader CO, Franke I, Schaller HC (2000) Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci 113(Pt 24):4475–4485 source
    • cites [9] Christensen SK, Narimatsu Y, Simoes S, Goth CK, Vægter CB, Small SA, et al. Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer’s-associated protein sorLA. bioRxiv. 2020;2020.07.12.199885. source

      The Discussion says newly synthesized sorLA is glycosylated in the ER and cis-Golgi and can reach the cell surface; the Introduction identifies N- and O-glycosites, and the paper describes immature and mature forms. But the paper’s model qualifies the proposed sequence: immature sorLA can reach the surface without normal Golgi maturation of its N-glycans, acquiring that maturation only after endocytosis and retrograde trafficking (Abstract; Discussion). The claim does not preserve that distinction. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Most protein-truncating SORL1 variants lead to reduced SorLA levels through nonsense-mediated decay and/or to putative production of truncated proteins and hence increased Aβ production.

    “as most PTVs lead to reduced SorLA levels through nonsense-mediated decay (NMD) [22, 23, 26] and/or to the putative production of truncated proteins and hence increased Aβ production”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [22] Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B et al (2016) SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Mol Psychiatry 21:831–836 source
    • cites [23] Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S et al (2012) High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry 17:875–879 source
    • cites [26] Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A et al (2016) A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease. Acta Neuropathol 132:213–224 source

      The Results (SORL1 mutation screening; page unavailable) predict that eight premature-termination variants cause haploinsufficiency through nonsense-mediated decay, and show reduced SORL1 RNA for one carrier. The citation is attached to the NMD claim, but the paper does not establish that most variants reduce SorLA protein levels: decay was tested for only one variant, and protein levels were not measured. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Exome and genome sequencing identified TREM2, SORL1, and ABCA7 as genes harboring a higher burden of rare non-synonymous variants in AD cases as compared to controls.

    “Exome and genome sequencing recently allowed the identification of three genes harboring a higher burden of rare non-synonymous variants in AD cases as compared to controls: TREM2, SORL1, and ABCA7 [2].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G et al (2017) Contribution to Alzheimer’s disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging 59:220.e1–220.e9 source

  • It may state two separate claims as one.

    Findingown data

    R332W, S577P and R654W show diverse degrees of subcellular mislocalization, with a smaller proportion of SorLA in early endosomes and a higher proportion in the endoplasmic reticulum, consistent with trafficking defects leading to partial retention in this compartment.

    “In contrast, the three maturation-defective variants (R332W, S577P and R654W) show diverse degrees of subcellular mislocalization, with a smaller proportion of SorLA in early endosomes and a higher proportion of SorLA in the endoplasmic reticulum, consistent with trafficking defects leading to their partial retention in this compartment.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    None of the 15 variants involves an Asparagine potentially involved in N-glycosylation anchoring, nor creates ER-resident motifs such as KDEL and dilysine.

    “None involves an Asparagine (N) potentially involved in N-glycosylation anchoring. Nor do they create ER-resident motifs, such as KDEL and dilysine.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    S577P hiPSCs show an intermediate SorLA distribution, with fewer large vesicles close to the nucleus and larger amounts of small vesicles dispersed in the cytoplasm compared to wild-type cells.

    “The S577P hiPSCs showed an intermediate distribution of SorLA, with fewer large vesicles close to the nucleus and larger amounts of small vesicles dispersed in the cytoplasm compared to the wild-type cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The variation of the M1 coefficient for Rab5 was less pronounced for the S577P variant.

    “Again, the variation of the M1 coefficient was less pronounced for the S577P variant (Fig. 7b, Additional file 6: Table S4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Some variants (S124R, R332W, G511R) introduced both in the SorLA759 and SorLA2131 constructs yielded similar quantitative results.

    “Note that some variants (S124R, R332W, G511R) have been introduced both in the SorLA759 and SorLA2131 constructs and yielded similar quantitative results.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Two SORL1 variants affecting proper maturation of SorLA were associated with an increase of Aβ secretion in the cellular medium, providing a direct link with AD pathophysiology.

    “We also demonstrated that two variants affecting the proper maturation of SorLA were associated with an increase of Aβ secretion in the cellular medium, thus providing a direct link with AD pathophysiology.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The rare SORL1 missense variants selected from AD patients are relevant to AD risk.

  • It may state two separate claims as one.

    Findingown data

    In R332W, the substitution gave rise to additional contacts such as cation-π interactions with R279 and loss of the hydrogen bond with D304; other interactions were altered from polar or ionic to hydrophobic.

    “In the R332W variant, the substitution of a long polar by a bulky aromatic sidechain gave rise to additional contacts, such as cation-π interactions with R279 and to the loss of the hydrogen bond with D304 (Fig. 10B and B′). Other existing interactions were altered, going from polar or ionic to hydrophobic.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    For WT SorLA2131 and SorLA759, the species present in the lysate were immature high-mannose type N-glycans, whereas the secreted forms corresponded to mature complex N-linked glycoproteins.

    “Treatment of WT SorLA2131 and SorLA759 proteins with glycosidase showed that the species present in the lysate were immature high-mannose type N-glycans (PNGase F and Endo H sensitive, Neu insensitive), whereas the secreted forms of the protein corresponded to mature complex N-linked glycoproteins (PNGase F and Neu sensitive, Endo H partially resistant) (Fig. 2d–g).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Treatment with neuraminidase altered the mobility of only the upper SorLA band, indicating that the upper species corresponds to complex type N-glycans capped with sialic acid residues.

    “Treatment with neuraminidase altered the mobility of only the upper band that subsequently migrated as the lower form, indicating that the upper species correspond to complex type N-glycans capped with sialic acid residues (Fig. 2a).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    R332W and R654W mutants led to significantly higher Aβ40 secretion (121.4 ± 14.4, p < 0.01 and 127.2 ± 19.6, p < 0.001, respectively).

    “In contrast, the R332W and R654W mutants, which showed the most obvious effect on SorLA maturation, led to significantly higher Aβ40 secretion (121.4 ± 14.4 p < 0.01 and 127.2 ± 19.6 p < 0.001, respectively).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The variation of the M1 coefficient for Cyclophilin B was less pronounced for the S577P variant.

    “Note that the variation of the M1 coefficient was less pronounced for the S577P variant (Fig. 7a, Additional file 6: Table S4).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    R332W and S577P clones show an intermediate SorLA migration profile, with decreased upper band intensity and increased lower band intensity, more pronounced for R332W.

    “Regarding the R332W and the S577P clones, we detected an intermediate profile, with a decrease in the intensity of the upper band and concomitantly an increase in the intensity of the lower band, appearing to be more pronounced for the R332W line (Fig. 5b).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Glycosidase treatment confirmed that the upper SorLA band corresponds to mature complex N-linked glycoproteins and the lower band to immature high-mannose type N-glycans.

    “Glycosidase treatment confirmed that the upper band corresponded to mature complex N-linked glycoproteins (PNGase F and Neu sensitive, Endo H partially resistant), and the lower band to immature high-mannose type N-glycans (PNGase F and Endo H sensitive, Neu insensitive) (Fig. 5a).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The amount of SorLA protein at the plasma membrane correlated with the amount of the mature form, with R654W showing the strongest effect and almost no detectable protein at the plasma membrane.

    “The amount of SorLA protein at the plasma membrane correlated with the amount of the mature form, the R654W showing the strongest effect with almost no detectable protein at the plasma membrane.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The R729W variant resulted in a lower level of secretion but did not reach statistical significance.

    “The R729W variant also resulted in a lower level of secretion, but did not reach statistical significance.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    R332W, S577P and R654W SorLA variants expressed at endogenous levels in hiPSCs exhibit diverse degrees of maturation defects and lower levels of mature protein at the plasma membrane.

    “Altogether, these data obtained in hiPSC lines expressing the R332W, S577P and R654W missense SORL1 variants at endogenous levels confirmed that these SorLA variants exhibit diverse degrees of maturation defects and lower levels of mature protein at the plasma membrane.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The S577P variant results in lower levels of SorLA at the plasma membrane, but levels are not statistically different from wild-type after correction for multiple testing.

    “The presence of the S577P variant also resulted in lower levels of SorLA at the plasma membrane, but levels were not statistically different from the wild-type form after correction for multiple testing.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    SorLA exists as two species in HEK293 cells: a mature complex-glycosylated form corresponding to the upper band and an immature oligomannoside N-linked core-glycosylated form corresponding to the lower band.

    “Together, these data indicated that SorLA exists as two species in HEK293 cells: a mature complex-glycosylated form of SorLA that corresponds to the upper band of the doublet and an immature oligomannoside N-linked core-glycosylated form of the protein that corresponds to the lower band.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Significant amounts of mature forms of R332W and S577P SorLA mutant proteins were produced in hiPSCs, in contrast to R654W which was barely detected as mature species.

    “In contrast to the R654W variant that was barely detected as mature species, significant amounts of mature forms of R332W and S577P SorLA mutant proteins were produced in hiPSCs, raising the question of their functionality regarding APP metabolism.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In HEK293 cells, altered SorLA maturation profile correlated with defects in SorLA targeting to the plasma membrane and lower SorLA levels at the plasma membrane.

    “In HEK293 cells, altered maturation profile correlated to defects in SorLA targeting to the plasma membrane, and lower SorLA levels at the plasma membrane.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    WT-SorLA759 and WT-SorLA2131 proteins were detected both in the cellular lysate and in the medium, indicating that both truncated constructs reached the plasma membrane and were efficiently secreted.

    “The WT-SorLA759 and WT-SorLA2131 proteins were detected both in the cellular lysate and in the medium (Fig. 3b, Additional file 1: Fig. S2), indicating that both truncated constructs reached the plasma membrane and were efficiently secreted.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Compared to WT, all SorLA variants exhibiting maturation defects showed a lower amount of biotinylatable cell-surface SorLA, with a less drastic effect for variants located in the Fibronectin-type III domain.

    “Compared to the wild-type form of the protein, all SorLA variants exhibiting maturation defects (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) showed a lower amount of biotinylatable cell-surface SorLA, with a less drastic effect for the variants located in the Fibronectin-type III domain.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The associated residues were either buried, partially buried, or partially exposed but did not correspond to residues maintaining the integrity of the Vps10p ten-bladed β-propeller or 10CC domains.

    “The associated residues were either buried (G543E) or partially buried (S564G, S577P, R654W, Fig. 9c, d) or partially exposed (S114R, R332W, R729W, Fig. 9a, b) but did not correspond to residues maintaining the integrity of Vps10p ten-bladed β-propeller or 10CC domains.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Endo H digestion of SorLA yielded two bands with reduced molecular size; the lower SorLA species were equally sensitive to Endo H and PNGase F, indicating they correspond to species bearing high mannose N-glycans.

    “In our experiments, Endo H digestion yielded two bands with reduced molecular size (Fig. 2c). As expected, the upper band that corresponds to mature complex type N-glycans capped with sialic acid residues, was somewhat resistant to Endo H. However, the lower SorLA species were equally sensitive to treatment with Endo H and PNGase F yielding a band at ~ 250 kDa, indicating that they correspond to”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In gnomAD v2.1.1 non-neuro subset, variant frequency ranged from full absence (R654W) to 4 individuals (R332W), 9 individuals (S577P) and 304 individuals (N371T) out of 114,679 controls.

    “Indeed, the frequency in large control databases such as gnomAD v2.1.1, non-neuro subset, ranged from a full absence (R654W), to the presence in 4 individuals (R332W), 9 indididuals (S577P) and 304 individuals (N371T), out of 114,679 controls.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The S124R variant is recurrent among AD cases (2 French cases, through two distinct genomic changes) and is absent in controls and in the gnomAD database.

    “Conversely, the S124R variant, which is recurrent among AD cases (2 French cases, through two distinct genomic changes), is absent in controls and in the gnomAD database.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    The gradual effect could be due to different severities of the folding defect and/or the ability of the ER quality control system to correct these.

    “This could be due to different severities of the folding defect present in the mutated protein and/or the ability of the ER quality control system to correct these.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    SORL1 knockout hiPSCs were used as a negative control.

    “SORL1 knockout (KO) hiPSCs were used as a negative control (Fig. 6, Additional file 1: Fig. S5).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Integration of each mutation was verified by sequencing.

    “Integration of the mutation was verified by sequencing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one. The quote only partly states this claim.

    Study design and conductown data

    FUS was used as a control and no FUS staining was detected in the biotinylated fraction, demonstrating the integrity of the plasma membrane during the biotinylation experiment.

    “The cytosolic FUS protein was used as a control to exclude non-specific labelling of the intracellular fractions. As expected, no FUS staining was detected in the biotinylated fraction.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The effect of R332W on extracellular Aβ levels may result from an insufficient amount of mature SorLA protein in appropriate cellular compartments and/or a direct impact of this variant on SorLA function on APP metabolism.

    “This effect on extracellular Aβ levels may result from an insufficient amount of mature SorLA protein in the appropriate cellular compartments to ensure its function with respect to APP metabolism, and/or a direct impact of this variant on SorLA function on APP metabolism, both not being exclusive.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisereasoning

    The functional effect of SORL1 missense variants and their pathophysiological mechanisms are hard to predict, and whether a given missense variant behaves as a loss-of-function variant remains to be determined for most of them.

    “In addition, contrary to PTVs, the functional effect of missense variants and their pathophysiological mechanisms are hard to predict. Whether or not a given missense variant behaves as a loss-of-function variant and by which mechanisms remain to be determined for most of them.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    The cytosolic FUS protein was used as a control to exclude nonspecific labelling of intracellular fractions, and no FUS staining was detected in the biotinylated fraction.

    “The cytosolic FUS protein was used as control to exclude nonspecific labelling of the intracellular fractions. As expected, no FUS staining was detected in the biotinylated fraction.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    SorLA is involved in the trafficking and recycling of APP; by binding to the retromer complex, SorLA redirects APP from early endosomes back to the Golgi apparatus, reducing amyloidogenic processing of APP.

    “First, SorLA is involved in the trafficking and recycling of APP. By binding to the retromer complex, SorLA redirects APP from the early endosomes back to the Golgi apparatus through the recycling pathway. This in turn results to reduced amyloidogenic processing of APP, by preventing it from being targeted to the late endosome compartments, where APP is cleaved into Aβ by the β- and γ-secretases.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Schmidt V, Subkhangulova A, Willnow TE (2017) Sorting receptor SORLA: cellular mechanisms and implications for disease. Cell Mol Life Sci 74:1475–1483 source
    • cites [20] Andersen OM, Rudolph I-M, Willnow TE (2016) Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease. Acta Neuropathol 132:653–665 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Cell lines were confirmed to be free of mycoplasma.

    “Cell lines were confirmed to be free of mycoplasma.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Integrity of the SorLA759 and SorLA2131 cDNA constructs was verified by sequencing.

    “Integrity of the SorLA759 and SorLA2131 cDNA constructs were verified by sequencing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The plasmidic constructs with the 15 listed SorLA variants were sequenced in their entirety.

    “The plasmidic constructs with S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S SorLA variants were sequenced in their entirety.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Interpretationreasoning

    Alteration of interatomic interactions could result in subtle variations of the protein 3D structure and folding stability.

    “Alteration of the interatomic interactions could result in subtle variations of the protein 3D structure and folding stability.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Aggregating protein-truncating SORL1 variants in cases and controls showed odds ratios ranging from ~12 to ~28 among all AD and EOAD cases, respectively.

    “Indeed, aggregating protein-truncating SORL1 variants (PTV, all of which are ultra-rare) in cases and controls showed odds ratios ranging from ~ 12 to ~ 28, among all AD and EOAD cases, respectively [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Campion D, Charbonnier C, Nicolas G (2019) SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol 138:173–186 source

  • It may state two separate claims as one.

    Interpretationown data

    The results obtained in HEK293 cells were validated in CRISPR/Cas9-modified hiPSCs, highlighting gradual effects of the variants.

    “Three of these variants and two maturation-competent variants were further studied in details on endogenous SORL1 in CRISPR/Cas9-modified hiPSCs, validating the results obtained in HEK293 cells and highlighting gradual effects of the variants.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Statistical models were adjusted for experiment settings.

    “Models were all adjusted for experiment settings.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    The absence of SorLA protein in SORL1-KO clones was verified using Western blotting.

    “The absence of the protein was then verified using Western blotting (Additional file 1: Fig S5).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Retention of the R332W, S577P, and R654W SorLA variants in the endoplasmic reticulum results in reduced delivery of mature SorLA protein to the plasma membrane and to the endosomal system.

    “We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisereasoning

    Due to their extreme rarity and diversity, it remains impossible to assess the association of rare SORL1 missense variants with AD at the variant level.

    “Due to their extreme rarity and diversity, it remains impossible to assess the association of rare SORL1 missense variants with AD at the variant level.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    SORL1 is a major AD risk factor gene, with increased frequencies of rare coding variant carriers in cases compared to cognitively healthy controls.

    “SORL1 is now considered as a major AD risk factor gene, because of increased frequencies of rare coding variant carriers in cases as compared to cognitively-healthy controls [2, 22–24].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [2] Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G et al (2017) Contribution to Alzheimer’s disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging 59:220.e1–220.e9 source
    • cites [22] Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B et al (2016) SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Mol Psychiatry 21:831–836 source
    • cites [23] Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S et al (2012) High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry 17:875–879 source
    • cites [24] Campion D, Charbonnier C, Nicolas G (2019) SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol 138:173–186 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Defects in protein trafficking and ER retention are a common cellular mechanism involved in the pathogenesis of a wide range of inherited human diseases, such as cystic fibrosis or kidney diseases.

    “Defects in protein trafficking and ER retention have been shown to be a common cellular mechanism involved in the pathogenesis of a wide range of inherited human diseases, such as cystic fibrosis [44] or kidney diseases [45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Welsh MJ, Smith AE (1993) Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 73:1251–1254 source
    • cites [45] Schaeffer C, Creatore A, Rampoldi L (2014) Protein trafficking defects in inherited kidney diseases. Nephrol Dial Transplant 29 Suppl 4:iv33–44 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    P-values were adjusted for multiple testing using Bonferroni's correction.

    “We adjusted p-values for multiple testing using the Bonferroni’s correction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    SorLA may directly bind nascent Aβ peptides and target them to lysosomes, contributing to the reduction of Aβ secretion.

    “Second, SorLA may directly bind nascent Aβ peptides and target them to lysosomes, which also contributes to the reduction of Aβ secretion [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Caglayan S, Takagi-Niidome S, Liao F, Carlo A-S, Schmidt V, Burgert T, et al (2014) Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation. Sci Transl Med 6:223ra20 source

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationreasoning

    In the early years, the quantity and quality of SorLA protein encoded by the wild-type allele, and potentially by the mutated allele, is sufficient to ensure protein function in patients heterozygous for SORL1 missense variants.

    “In patients, SORL1 missense variants are found at the heterozygous state, and we can expect that in the early years, the quantity and quality of SorLA protein encoded by the wild-type allele, and potentially by the mutated allele, is sufficient to ensure protein function.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In patients, SORL1 missense variants are found at the heterozygous state.

  • It may state two separate claims as one.

    Interpretationreasoning

    A subset of the variants induced a likely misfolded protein, thus altering protein maturation and trafficking, and eventually leading to a loss of the protective function of SorLA towards Aβ secretion.

    “A subset of the variants induced a likely misfolded protein, thus altering the protein maturation and trafficking, and eventually leading to a loss of the protective function of SorLA towards Aβ secretion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Interpretationown data

    The existence of two distinct genomic changes leading to the same missense change in two unrelated patients suggests that this amino acid position should be further studied in other models.

    “Thus, the existence of two distinct genomic changes leading to a same missense change in two unrelated patients suggests that this amino acid position should be further studied in other models, as for the S577P, and despite the absence of modification of Aβ secretion in hiPSCs after 24 h secretion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationown data

    We cannot exclude specific effects of SorLA variants during aging conditions or cell-specific effects.

    “As we cannot exclude specific effects of SorLA variants during aging conditions, neither can we exclude a cell-specific effect.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationnone given

    As individuals age, the decline in cellular quality control systems will lead to production of more non-functional proteins, resulting in a progressive loss of SorLA function.

    “However, as individuals age, the decline in cellular quality control systems will lead to the production of more and more non-functional proteins, resulting in a progressive loss of SorLA function.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Age-associated deterioration of cellular machinery leads to an increase in the occurrence of protein misfolding, accumulation and aggregation, due in part to the gradual decay of ER chaperoning systems.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    It is possible that the S577P variant has a long-term effect that would not be featured by short-term culture experiments.

    “It is therefore possible that this S577P variant, identified in AD patients, has a long-term effect that would not be featured by our short-term culture experiments.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Age-associated deterioration of cellular machinery leads to an increase in the occurrence of protein misfolding, accumulation and aggregation, due in part to the gradual decay of ER chaperoning systems.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    Our data do not preclude any role for variants identified in AD patients that did not display drastic maturation and transport defects in our cellular model.

    “Regarding the variants identified in AD patients that did not display drastic maturation and transport defects in our cellular model, our data do not preclude any role for these variants in the AD neurodegenerative process.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    In our cellular model, the amount of mature protein produced for S577P is sufficient and this mutant protein is functional regarding APP metabolism.

    “This indicates that, in our cellular model, the amount of mature protein produced is sufficient and that this mutant protein is functional regarding APP metabolism.”
    Quote in the paperSubstantial claim
62 of 62

  • The paper relies on this without support.

    The Vps10p domain structure (PDB ID 3WSY) is representative of the full-length SorLA protein for assessing the impact of missense variants on protein 3D structure.

    “The structure of the Vps10p domain of SorLA in complex with its own propeptide fragment (PDB ID 3WSY) was used as a model for structural analysis [38].”

  • The paper relies on this without support.

    The rare SORL1 missense variants selected from AD patients are relevant to AD risk.

    “SORL1 rare missense variants were selected among a series of 1383 exomes of unrelated probands with AD (EOAD in 97% of cases) from the national reference center for young Alzheimer patients (CNRMAJ, Rouen, France).”

  • The paper relies on this without support.

    The bioinformatic tools PolyPhen-2, SIFT and MutationTaster accurately classify SORL1 missense variants as deleterious.

    “classified them into Mis 0, 1 2 or 3 categories depending on the number of bioinformatics tools predicting the variant to be deleterious or not among Polyphen-2, SIFT and Mutation Taster.”

  • The authors state this as an assumption.

    The impact of the R332W and S577P variants on protein conformation in this cellular model is more moderate, and the folding process is able to occur, at least partially.

    “We can assume that the impact of the R332W and S577P variants on protein conformation in this cellular model are more moderate, and that the folding process is able to occur, at least partially.”

  • The paper relies on this without support.

    In patients, SORL1 missense variants are found at the heterozygous state.

    “In patients, SORL1 missense variants are found at the heterozygous state”

  • The paper relies on this without support.

    Age-associated deterioration of cellular machinery leads to an increase in the occurrence of protein misfolding, accumulation and aggregation, due in part to the gradual decay of ER chaperoning systems.

    “Indeed, age-associated deterioration of cellular machinery leads to an increase in the occurrence of protein misfolding, accumulation and aggregation, due in part to the gradual decay of ER chaperoning systems.”

  • The paper relies on this without support.

    ER-retained proteins are typically degraded in a pre-Golgi compartment.

    “ER-retained proteins are typically degraded in a pre-Golgi compartement.”

  • The paper relies on this without support.

    Mutations act by impacting protein folding and conformational stability, thus interfering with efficient post-translational modification and subsequent protein trafficking.

    “Mutations act by impacting protein folding and conformational stability, thus interfering with efficient post-translational modification and subsequent protein trafficking.”
8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Wild-type-maturation variant count conflicts with the listed variants

    Minor

    The later statement says there are 13 such variants but names only 10. The earlier selection names 12, including Y141C and N371T, which are absent from the later list.

  • Variants outside the stated Vps10p boundaries are treated as Vps10p variants

    Minor

    The structural analysis treats S114R and S124R as variants localized in the Vps10p domain, but the paper defines that domain as amino acids 136-752. Positions 114 and 124 fall outside those boundaries.

  • LDLR class A domain is incorrectly described as unaffected

    Minor

    The paper says none of the 15 maturation-defective variants is in the LDLR class A repeats, although its own domain boundaries place the listed variants D1535N and D1545E within that domain.

3 of 3

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Metadata

Authors
Rovelet-Lecrux, A., Feuillette, S., Miguel, L., Schramm, C., Pernet, S., Quenez, O., Ségalas-Milazzo, I., Guilhaudis, L., Rousseau, S., Riou, G., Frébourg, T., Campion, D., Nicolas, G., & Lecourtois, M.
Affiliations
  • Inserm (FR)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Lecourtois, Magalie
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2021-12-18
Volume
9
Issue
1
Pages
196-196
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-021-01294-4
PMC
PMC8684260
OpenAlex
W4226077512
Cited by
38
References
46
Citations by year
2026: 6 · 2025: 9 · 2024: 8 · 2023: 9 · 2022: 5 · 2021: 1
FWCI
2.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Association France Alzheimer (AAPSM2019 – grant n°1957)
  • Fondation pour la Recherche médicale (grant # DEQ20170336711, grant #ARF201909009263)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
SORL1, SorLA, Alzheimer's disease, missense mutations, protein maturation, protein trafficking, endoplasmic reticulum retention, amyloid-beta secretion, loss of function, human induced pluripotent stem cells, protein structure
MeSH terms
Alzheimer Disease, Humans, Mutation, Missense, LDL-Receptor Related Proteins, Membrane Transport Proteins, HEK293 Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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