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Cited by 116Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index; 9 of the 29 sources its claims cite were checked for support.

LRP1 is a neuronal receptor for α-synuclein uptake and spread

Open access
Chen, Kai, Martens, Yuka A., Meneses, Axel, Ryu, Daniel H., Lu, Wenyan, Raulin, Ana Caroline, Li, Fuyao, Zhao, Jing, Chen, Yixing, Jin, Yunjung, Linares, Cynthia, Goodwin, Marshall, Li, Yonghe, Liu, Chia-Chen, Kanekiyo, Takahisa, Holtzman, David M., Golde, Todd E., Bu, Guojun, Zhao, Na·2022·Molecular Neurodegeneration
DOI 10.1186/s13024-022-00560-wPMC PMC9438229
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Abstract

Background: The aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson’s disease (PD) and Lewy body dementia (LBD). Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood. Methods: We established LRP1 knockout (LRP1-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using a CRISPR/Cas9 strategy and generated iPSC-derived neurons (iPSNs) to test the role of LRP1 in α-Syn uptake. We treated the iPSNs with fluorescently labeled α-Syn protein and measured the internalization of α-Syn using flow cytometry. Three forms of α-Syn species were tested: monomers, oligomers, and pre-formed fibrils (PFFs). To examine whether the lysine residues of α-Syn are involved in LRP1-mediated uptake, we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization. We also tested whether the N-terminus of α-Syn is critical for LRP1-mediated internalization. Lastly, we investigated the role of Lrp1 in regulating α-Syn spread with a neuronal Lrp1 conditional knockout (Lrp1-nKO) mouse model. We generated adeno-associated viruses (AAVs) that allowed for distinguishing the α-Syn expression versus spread and injected them into the hippocampus of six-month-old Lrp1-nKO mice and the littermate wild type (WT) controls. The spread of α-Syn was evaluated three months after the injection. Results: We found that the uptake of both monomeric and oligomeric α-Syn was significantly reduced in iPSNs with LRP1-KO compared with the WT controls. The uptake of α-Syn PFFs was also inhibited in LRP1-KO iPSNs, albeit to a much lesser extent compared to α-Syn monomers and oligomers. The blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in iPSNs and the N-terminus of α-Syn was critical for LRP1-mediated α-Syn uptake. Finally, in the Lrp1-nKO mice, the spread of α-Syn was significantly reduced compared with the WT littermates. Conclusions: We identified LRP1 as a key regulator of α-Syn neuronal uptake, as well as an important mediator of α-Syn spread in the brain. This study provides new knowledge on the physiological and pathological role of LRP1 in α-Syn trafficking and pathology, offering insight for the treatment of synucleinopathies.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Using LRP1-knockout human iPSC-derived neurons and neuronal Lrp1 conditional knockout mice, this study identifies LRP1 as a key regulator of α-synuclein neuronal uptake and spread. LRP1 primarily mediates soluble monomeric and oligomeric α-synuclein via lysine residues in the α-synuclein N-terminus, with much weaker dependence for preformed fibrils.

Key findings

  • LRP1-KO iPSNs showed significantly reduced uptake of monomeric α-synuclein (>75% reduction) and oligomeric α-synuclein (~50% reduction), while α-synuclein PFF uptake was only mildly inhibited (~5–10% reduction).
  • Capping lysine residues on α-synuclein decreased its uptake by ~50%; LRP1-KO inhibited uptake of the N-terminal α-synuclein fragment similarly to full-length α-synuclein but had no effect on the ΔN fragment, and excess non-labeled N-terminal fragment competed with full-length α-synuclein uptake whereas ΔN did not.
  • In Lrp1-nKO mice, h-α-synuclein spread to the cortex was significantly reduced compared with WT littermates, while hippocampal GFP and h-α-synuclein signals did not differ significantly between groups.
  • As validation, tau uptake was reduced by ~90% in LRP1-KO iPSNs compared with WT.

Methods

  • Human iPSCs from a healthy 83-year-old female APOE3/3 donor were edited with CRISPR/Cas9 to generate LRP1-KO isogenic lines, differentiated into iPSNs, and assayed by flow cytometry for uptake of fluorescently labeled α-synuclein monomers, oligomers, PFFs, N-terminal and ΔN fragments, lysine-capped α-synuclein, tau, and transferrin; RAP competition and electron microscopy were also used.
  • Lrp1flox/flox mice crossed with CaMKII-Cre mice on an APOE3/3 background received stereotactic hippocampal injections of AAV-synapsin-GFP-synapsin-h-α-Synuclein at 6 months of age; α-synuclein spread was assessed 3 months later by immunofluorescence and Western blotting (n = 5 WT, n = 6 Lrp1-nKO for imaging analyses).
  • Data are reported as mean ± s.d.; comparisons used unpaired t tests or one-way ANOVA with Tukey’s multiple comparison test, two-sided.

Limitations

  • The paper states that whether other cell types, such as astrocytes and microglia, can take up and spread tau and α-synuclein via LRP1 needs further investigation, and that how LRP1, HSPGs, and APOE together affect tau and α-synuclein uptake and spread requires further study.
  • Evident from the text: the iPSC experiments rely on a single parental iPSC line from one 83-year-old female APOE3/3 donor and two LRP1-KO clones, and the in vivo spread assay uses one injection site, one age, and one post-injection time point in an APOE3/3 background.
  • Evident from the text: because LRP1-KO only mildly reduced PFF uptake, the strongest conclusions concern soluble monomeric and oligomeric α-synuclein rather than fibrillar α-synuclein.

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

Integrity signals

Registry

Crossref · 10.1186/s13024-022-00560-w

Cites

64 of 64 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

9 of 29 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The aspartic acid residues in each complement-type repeat can form an acidic pocket responsible for docking lysine residues on ligands.

    “The aspartic acid residues in each repeat can form acidic pocket responsible for docking the lysine residues on ligands [37].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev. 2008;88:887–918. source
  • Findingown data

    Blocking lysine residues on α-Syn with sulfo-NHS acetate decreased α-Syn uptake in iPSNs by approximately 50%.

    “We found that the blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in the iPSNs (~ 50% reduction) (Fig. 3b)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Capping lysine residues on α-Syn with sulfo-NHS acetate specifically blocks lysine residues without otherwise altering α-Syn uptake.
  • Findingown data

    Blocking lysine residues on α-Syn effectively decreased uptake of α-Syn in iPSNs.

    “The blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in iPSNs and the N-terminus of α-Syn was critical for LRP1-mediated α-Syn uptake.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: α-Syn has a similar high content (10%) of lysines as tau.
  • Findingown data

    Internalized tau was reduced by ~90% in LRP1-KO iPSNs compared to WT cells.

    “We confirmed that the amount of internalized tau proteins was reduced by ~ 90% in LRP1-KO iPSNs compared to WT cells (Fig. 1f and g), consistent with what has been reported previously.”
    Quote in the paperSubstantial claim
  • Findingown data

    LRP1-deficiency significantly reduced neuronal α-Syn uptake in LRP1-KO iPSNs generated by CRISPR/Cas9.

    “We found that LRP1-deficiency significantly reduced neuronal α-Syn and tau uptake using LRP1-KO iPSNs generated by the CRISPR/Cas9 technique.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 9
  • It may state two separate claims as one. 13

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

    Premisecitation

    Oligomeric α-Syn species appear prone to uptake and spread from cell-to-cell in a prion-like manner, leading to templated misfolding of native α-Syn and formation of aggregates throughout the brain.

    “Particularly, the oligomeric α-Syn species appear to be prone to uptake and spread from cell-to-cell in a prion-like manner, leading to the templated misfolding of the native forms of α-Syn and formation of α-Syn aggregates throughout the brain, which are the defining pathological features of Parkinson’s disease (PD) and dementia with Lewy body (DLB) [12–19].”
    Quote in the paperSubstantial claim2 of 8 sources checked
    • cites [12] Brundin P, Melki R, Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2010;11:301–7. source

      In “Grafted cells develop Lewy bodies” (page unavailable), the review reports uptake of α-synuclein oligomers in cultured neurons and seeding of endogenous α-synuclein aggregates. It also suggests that non-native α-synuclein can spread between cells and affect progressively greater parts of the central nervous system in Parkinson’s disease. It does not establish that oligomers specifically drive spread throughout the brain, or address dementia with Lewy bodies as the citing sentence does. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [13] Angot E, Steiner JA, Hansen C, Li JY, Brundin P. Are synucleinopathies prion-like disorders? The Lancet Neurology. 2010;9:1128–38. source
    • cites [14] Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017;18:101–13. source
    • cites [15] Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A, Kretzschmar H, Hengerer B, Kostka M. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci. 2007;27:9220–32. source
    • cites [16] Danzer KM, Krebs SK, Wolff M, Birk G, Hengerer B. Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. J Neurochem. 2009;111:192–203. source
    • cites [17] Luk KC, Song C, O’Brien P, Stieber A, Branch JR, Brunden KR, Trojanowski JQ, Lee VM. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106:20051–6. source
    • cites [18] Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, et al. alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011;121:715–25. source

      The Discussion reports cell-to-cell α-syn transfer and seeding in the study’s models, and describes templated spread through progressively greater parts of the PD nervous system as a hypothesis. It does not establish that oligomers are particularly prone to uptake: the Discussion says monomeric, oligomeric, and fibrillar forms can all be internalized. Nor does it demonstrate aggregate formation throughout the brain. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [19] Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW. Neuropathology and molecular diagnosis of Synucleinopathies. Mol Neurodegener. 2021;16:83. source

  • Probably not a substantial claim.

    Premisecitation

    LRP1 mediates and regulates the endocytosis of more than 30 ligands, including apolipoprotein E (APOE) and amyloid-β (Aβ).

    “LRP1 mediates and regulates the endocytosis of > 30 ligands, including apolipoprotein E (APOE) and amyloid-β (Aβ) [21–27]”
    Quote in the paperSubstantial claim6 of 7 sources checked
    • cites [21] Kanekiyo T, Bu G. The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease. Frontiers in aging neuroscience. 2014;6:93. source

      The Introduction and the Structural and Functional Features section describe LRP1 as an endocytic receptor for diverse ligands. The Summary and Perspective identifies apoE as a major LRP1 ligand, and the Mechanisms of LRP1-Regulated Cellular Aβ Uptake section describes LRP1-mediated Aβ endocytosis. Our copy does not give the claimed count of more than 30 ligands. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [22] Kanekiyo T, Cirrito JR, Liu CC, Shinohara M, Li J, Schuler DR, Shinohara M, Holtzman DM, Bu G. Neuronal clearance of amyloid-β by endocytic receptor LRP1. J Neurosci. 2013;33:19276–83. source

      The Introduction (page unavailable) lists apolipoprotein E among ligands taken up through LRP1, and the Results section reports LRP1-mediated Aβ uptake in neuronal cells. Our copy does not give the claimed count of more than 30 ligands. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [23] Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501–18. source

      The Biology of APOE section identifies LRP1 as an APOE receptor, and the Aβ clearance section describes LRP1-dependent cellular uptake of Aβ. Our copy does not support the specific claim that LRP1 mediates endocytosis of more than 30 ligands (searched: “LRP1 30 ligands” and “LRP1 more than 30 ligands endocytosis”). Page numbers were not available in the indexed passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [24] Zhao N, Liu CC, Qiao W, Bu G. Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol Psychiatry. 2018;83:347–57. source

      The ‘ApoE receptors’ section identifies LRP1 as an apoE-binding receptor, and ‘LRP1 in Aβ clearance’ reports that LRP1 affects neuronal Aβ uptake and trafficking. Our copy does not state that LRP1 mediates endocytosis of more than 30 ligands, so it does not support the claimed number. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [25] Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10:333–44. source
    • cites [26] Kanekiyo T, Bu G. The low-density lipoprotein receptor-related protein 1 and amyloid-beta clearance in Alzheimer’s disease. Front Aging Neurosci. 2014;6:93. source

      The Introduction describes LRP1 as regulating endocytosis of diverse ligands, and the Summary and Perspective identifies apoE as a major LRP1 ligand. The section on mechanisms of cellular Aβ uptake says LRP1 regulates Aβ endocytosis. Our copy does not give the claimed count of more than 30 ligands. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [27] Robert J, Button EB, Martin EM, McAlary L, Gidden Z, Gilmour M, Boyce G, Caffrey TM, Agbay A, Clark A, et al. Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E. Mol Neurodegener. 2020;15:23. source

  • It may state two separate claims as one.

    Findingown data

    LRP1-deficiency significantly reduced cellular uptake of monomeric α-Syn by more than 75% in iPSNs, consistent across two LRP1-KO clones.

    “We found that, similar to tau, LRP1-deficiency significantly reduced the cellular uptake of α-Syn (more than 75% reduction) in the iPSNs and consistent findings were observed from two different clones of LRP1-KO iPSNs (Fig. 2a, b, and c).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    RAP suppressed neuronal uptake of α-Syn in a dose-dependent manner, while transferrin internalization was not affected.

    “We found that RAP strongly suppressed the neuronal uptake of α-Syn in a dose-dependent manner, whereas transferrin internalization was not affected (Fig. 2f).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Addition of non-labeled N-α-Syn significantly inhibited uptake of full-length α-Syn in iPSNs, whereas ΔN-α-Syn had no effect.

    “we found that the addition of N-α-Syn significantly inhibited the uptake of full-length α-Syn, whereas ΔN-α-Syn had no effect (Fig. 3d).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The N-α-Syn and ΔN-α-Syn fragments are properly folded and their uptake reflects the role of the N-terminus.

  • It may state two separate claims as one.

    Findingown data

    LRP1 knockout effectively inhibited uptake of N-α-Syn to a similar extent as full-length α-Syn but had no effect on ΔN-α-Syn uptake in iPSNs.

    “We found that LRP1-KO effectively inhibited the uptake of N-α-Syn, to a similar extent as the full-length α-Syn but had no effect on ΔN-α-Syn uptake (Fig. 3c).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The N-α-Syn and ΔN-α-Syn fragments are properly folded and their uptake reflects the role of the N-terminus.

  • It may state two separate claims as one.

    Study design and conductown data

    After 14 days of culture, WT and LRP1-KO cells exhibited typical neuronal morphology and expressed neuronal marker Tuj1, indicating successful differentiation of NPCs into iPSNs.

    “After 14 days of culture, both WT and LRP1-KO cells exhibited a typical neuronal morphology and expressed the neuronal marker (Tuj1), suggesting the successful differentiation of NPCs into neurons (iPSNs) (Fig. 1c).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The strategy of deleting LRP1 in human iPSNs was successful and tau uptake was inhibited by LRP1 deletion in these cells.

    “Together, these data indicate that our strategy of deleting LRP1 in human iPSNs was successful and tau uptake was inhibited by LRP1 deletion in these cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    A recent study identified LRP1 as a key regulator for the uptake and spread of tau.

    “A recent study also identified LRP1 as a key regulator for the uptake and spread of microtubule-associated protein tau [29].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Leshuk C, Hernandez I, Wegmann S, Hyman BT, et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020;580:381–5. source

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

    Premisecitation

    LRP1 is a transmembrane receptor that belongs to the LDLR family.

    “The low-density lipoprotein receptor (LDLR)-related protein 1 (LRP1) is a transmembrane receptor that belongs to the LDLR family [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Herz J, Bock HH. Lipoprotein receptors in the nervous system. Annu Rev Biochem. 2002;71:405–34. source

  • It may state two separate claims as one.

    Premiseown data

    α-Syn has a high lysine content (15 lysines out of 140 aa, ~10%), with eleven lysines in the N-terminus, one in NAC, and three in C-terminus.

    “α-Syn has a high lysine content (15 lysines out of 140 aa, ~ 10%) with most (eleven) lysines located in the N-terminus, one lysine in NAC, and three in C-terminus (Fig. 3a).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    NPCs from WT and two LRP1-KO lines were positive for neural precursor marker Nestin.

    “we confirmed that all the NPCs from the three lines were positive for neural precursor marker (Nestin) by immunostaining (Fig. 1b).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    LAG3 specifically binds to α-Syn PFFs but not monomers.

    “Notably, LAG3 specifically binds to α-Syn PFFs but not monomers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353:aah3374. source

  • It may state two separate claims as one.

    Study design and conductown data

    Within the hippocampus, GFP and h-α-Syn signal showed no significant differences between Lrp1-nKO and WT mice, indicating equivalent transduction of AAVs between the two groups.

    “Within the hippocampus, both GFP and h-α-Syn signal showed no significant differences between Lrp1-nKO and WT mice, indicating equivalent transduction of AAVs between the two groups (Fig. 4e, f and g).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Karyotyping revealed preservation of normal chromosome number and appearance in each iPSC clone.

    “Karyotyping in each iPSC clones revealed the preservation of normal number and appearance of chromosomes (Fig. S2a).”
    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

    LAG3 is a receptor for α-Syn PFFs that mediates endocytosis and transmission of α-Syn PFFs between neurons.

    “A recent study showed that the lymphocyte-activation gene 3 (LAG3) is a receptor for α-Syn PFFs which mediates the endocytosis and transmission of α-Syn PFFs between neurons [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353:aah3374. source

  • It may state two separate claims as one.

    Interpretationreasoning

    When forming fibrils, the N-terminus of α-Syn is less exposed, so the interaction between α-Syn and LRP1 might be limited.

    “The finding may suggest that when forming the fibrils, the N-terminus of α-Syn is less exposed therefore the interaction between α-Syn and LRP1 might be limited.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Monomeric α-Syn is composed of three domains: a lipid binding N-terminus domain (aa 1-60), a hydrophobic non-amyloid component (NAC) domain (aa 61-95), and a negatively charged C-terminus domain (aa 96-140).

    “Monomeric α-Syn is composed of three domains: a lipid binding N-terminus domain (aa 1–60), a hydrophobic non-amyloid component (NAC) domain (aa 61–95), and a negatively charged C-terminus domain (aa 96–140) [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Meade RM, Fairlie DP, Mason JM. Alpha-synuclein structure and Parkinson’s disease - lessons and emerging principles. Mol Neurodegener. 2019;14:29. source

  • It may state two separate claims as one.

    Interpretationown data

    LRP1 is a key regulator for both α-Syn and tau uptake and spread.

    “Our findings support the hypothesis that LRP1 is a key regulator for both α-Syn and tau uptake and spread”
    Quote in the paperSubstantial claim
19 of 19

  • The paper relies on this without support.

    α-Syn has a similar high content (10%) of lysines as tau.

    “Notably, α-Syn has a similar high content (10%) of lysines as tau.”

  • The paper relies on this without support.

    The underlying cellular mechanisms of α-Syn uptake and spread remain poorly understood.

    “However, the underlying cellular mechanisms of α-Syn uptake and spread remains poorly understood.”

  • The paper relies on this without support.

    Secreted soluble α-Syn can be taken up by different cells.

    “Importantly, these secreted soluble α-Syn can be taken up by different cells.”

  • The paper relies on this without support.

    Capping lysine residues on α-Syn with sulfo-NHS acetate specifically blocks lysine residues without otherwise altering α-Syn uptake.

    “we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization of α-Syn in the iPSNs.”

  • The paper relies on this without support.

    The N-α-Syn and ΔN-α-Syn fragments are properly folded and their uptake reflects the role of the N-terminus.

    “We employed the α-Syn protein fragments containing only the N-terminus (N-α-Syn) or lacking the N-terminus (ΔN-α-Syn) of full-length α-Syn (Fig. 3a).”

  • The paper relies on this without support.

    LRP1-nKO mice have no compensatory mechanisms that restore LRP1 function or alter α-Syn spread independently of LRP1 deletion.

    “we used the conditional neuronal Lrp1 knockout mice [38] by crossing Lrp1flox/flox mice with CaMKII-Cre mice to generate Lrp1-nKO (Lrp1flox/flox; Cre+/−) and WT littermate controls (Lrp1flox/flox; Cre−/−).”
6 of 6

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.

  • Residues 37-97 are called N-terminal despite the stated domain boundaries

    Minor

    The Results define the N-terminus as residues 1-60, the NAC domain as 61-95, and the C-terminus as 96-140. The Discussion nevertheless calls residues 37-97 "N-terminal residues," although that range extends through the NAC domain and into the C-terminus.

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Kanekiyo T, Bu G. The low-density lipoprotein receptor-related protein 1 and amyloid-beta clearance in Alzheimer’s disease. Front Aging Neurosci. 2014;6:93. · DOI · Paper page
  2. Jin Y, Li F, Sonoustoun B, Kondru NC, Martens YA, Qiao W, Heckman MG, Ikezu TC, Li Z, Burgess JD, et al. APOE4 exacerbates alpha-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology. Acta Neuropathol. 2022;143:641. · DOI · Paper page

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Metadata

Authors
Chen, K., Martens, Y. A., Meneses, A., Ryu, D. H., Lu, W., Raulin, A. C., Li, F., Zhao, J., Chen, Y., Jin, Y., Linares, C., Goodwin, M., Li, Y., Liu, C.-C., Kanekiyo, T., Holtzman, D. M., Golde, T. E., Bu, G., & Zhao, N.
Affiliations
  • Mayo Clinic (US)
  • University of Florida (US)
  • Washington University in St. Louis (US)
Corresponding author
  • Bu, Guojun
  • Zhao, Na
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2022-09-02
Volume
17
Issue
1
Pages
57-57
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-022-00560-w
PMC
PMC9438229
OpenAlex
W4294168387
Cited by
115
References
64
Citations by year
2026: 31 · 2025: 40 · 2024: 26 · 2023: 15 · 2022: 3
FWCI
11.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • NIH (P01NS074969, U19AG069701)
  • Mayo Alzheimer’s Disease Research Center Developmental Grant
  • Lewy Body Dementia Center Without Walls (U54NS110435)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
alpha-synuclein, Parkinson's disease, dementia with Lewy bodies, protein uptake, prion-like spread, lysine residues, N-terminus, preformed fibrils, oligomers, lysosomal degradation, iPSC-derived neurons, neurodegeneration, tau spread, isogenic iPSC lines
MeSH terms
Animals, Humans, Infant, Parkinson Disease, Synapsins, tau Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Mice, alpha-Synuclein, Induced Pluripotent Stem 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 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (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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