Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus α-synuclein and β-amyloid aggregates
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Abstract
Abstract Transcellular propagation of aggregate “seeds” has been proposed to mediate progression of neurodegenerative diseases in tauopathies and α-synucleinopathies. We have previously determined that tau and α-synuclein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface. This mediates uptake and intracellular seeding. The specificity and mode of binding to HSPGs has been unknown. We used modified heparins to determine the size and sulfation requirements of glycosaminoglycan (GAGs) binding to aggregates in biochemical and cell uptake and seeding assays. Aggregates of tau require a precise GAG architecture with defined sulfate moieties in the N- and 6-O-positions, whereas α-synuclein and Aβ rely slightly more on overall charge on the GAGs. To determine the genetic requirements for aggregate uptake, we individually knocked out the major genes of the HSPG synthesis pathway using CRISPR/Cas9 in HEK293T cells. Knockout of EXT1, EXT2 and EXTL3, N-sulfotransferase (NDST1), and 6-O-sulfotransferase (HS6ST2) significantly reduced tau uptake. α-Synuclein was not sensitive to HS6ST2 knockout. Good correlation between pharmacologic and genetic manipulation of GAG binding by tau and α-synuclein indicates specificity that may help elucidate a path to mechanism-based inhibition of transcellular propagation of pathology.
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HSPGs are largely responsible for neuronal Tau uptake.
“Previous work showed that HSPGs are largely responsible for neuronal Tau uptake46–48,57.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [47]
The GAG length/sulfation section reports that HSPGs mediate tau aggregate uptake, and Figure 8 shows reduced uptake after HSPG-pathway gene knockouts in HEK293T cells. The paper says the requirements still need evaluation in post-mitotic central nervous system neurons, so it does not establish the claim specifically for neuronal uptake. Page numbers were not supplied. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHSPGs are essential players in the cellular uptake of Tau.
“Intriguingly, over the past decade, HSPGs have been revealed as essential players in the cellular uptake of Tau46–48.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [47]
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Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds
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Self-citationTau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs)
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- Authors
- Stopschinski, B. E., Holmes, B. B., Miller, G. M., Manon, V. A., Vaquer-Alicea, J., Prueitt, W. L., Hsieh-Wilson, L. C., & Diamond, M. I.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Washington University in St. Louis (US)
- California Institute of Technology (US)
- Corresponding author
- Diamond, Marc I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 293
- Issue
- 27
- Pages
- 10826-10840
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6036193
- OpenAlex
- W2801709935
- Cited by
- 180
- References
- 3
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 16 · 2023: 19 · 2022: 24 · 2021: 33 · 2020: 24 · 2019: 26 · 2018: 7
- FWCI
- 15.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- Funders
- RWTH University Aachen, Faculty of Medicine (Rotation Program for Junior Researchers)
- Rainwater Charitable Foundation (Tau Consortium)
- HHS | National Institutes of Health (NIH) (1F31NS079039)
- Medical Scientist Training Program, Washington University St. Louis (5T32GM07200)
- Cure Alzheimer's Fund (CAF)
- Carl B. and Florence E. King Foundation
- University of Texas Southwestern Medical Center (Medical Student Summer Research Fellowship)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- tau aggregates, alpha-synuclein aggregates, amyloid-beta aggregates, heparan sulfate proteoglycans, glycosaminoglycan sulfation, glycosaminoglycan chain length, tauopathy, synucleinopathies, exostosin 1, neurodegenerative diseases
- MeSH terms
- Exostosin 1, Exostosin 2, Glycosaminoglycans, Humans, Sulfur, Sulfotransferases, Amyloid beta-Peptides, tau Proteins, N-Acetylglucosaminyltransferases, Heparan Sulfate Proteoglycans, Tauopathies, alpha-Synuclein, CRISPR-Cas Systems
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