Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs)
Abstract
The misfolding and accumulation of tau protein into intracellular aggregates known as neurofibrillary tangles is a pathological hallmark of neurodegenerative diseases such as Alzheimer's disease. However, while tau propagation is a known marker for disease progression, exactly how tau propagates from one cell to another and what mechanisms govern this spread are still unclear. Here, we report that cellular internalization of tau is regulated by quaternary structure and have developed a cellular assay to screen for genetic modulators of tau uptake. Using CRISPRi technology we have tested 3200 genes for their ability to regulate tau entry and identified enzymes in the heparan sulfate proteoglycan biosynthetic pathway as key regulators. We show that 6-O-sulfation is critical for tau-heparan sulfate interactions and that this modification regulates uptake in human central nervous system cell lines, iPS-derived neurons, and mouse brain slice culture. Together, these results suggest novel strategies to halt tau transmission.
Additional Information
© 2018 the Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received: 08 June 2017; Accepted: 28 March 2018; Published online: 23 April 2018. We thank Jason Gestwicki (UCSF) for the 2N4R pRK172 plasmid, Bruce Conklin (UCSF) for the CRISPRi iPS cells, the UCSB NRI-MCDB Microscopy Facility for use of the TEM and Confocal Microscope, the UCSB Stem Cell Core for use of the facility, and the UCSB BNL for access to the DLS. J.J.C. was supported by a postdoctoral fellowship from the Alzheimer's Association and the QB3/Calico Longevity Fellowship. S.K.S. was supported by a National Defense Science & Engineering Graduate (NDSEG) Fellowship. A.W.S. was supported by an NIH Training Grant (NIH/NRSA 5T32 GM007616-38). L.C.H.-W. was supported by an NIH/NIGMS grant (R01 GM093627). Support also came from an NIH Director's New Innovator Award (NIH/NIGMS DP2 GM119139) (M.K.), an Allen Distinguished Investigator Award (Paul G. Allen Family Foundation) (M.K.), the Tau Center Without Walls (NIH/NINDS U54 NS100717) (M.K., K.S.K), the Tau Consortium (K.S.K.) the Chan-Zuckerberg Biohub (M.K.) and the Paul F. Glenn Center for Aging Research (M.K.). Author Contributions: J.N.R., J.J.C., A.W.S., G.M.M., and T.S. performed experiments and interpreted results. S.K.S. made and validated the H4 CRISPRi cell line. L.C.H.-W., M.K., and K.S.K., interpreted results and directed the research. J.N.R., J.J.C., L.C.H.-W., M.K., and K.S.K. wrote the manuscript. K.S.K. serves as a consultant and has shares in ADRx, serves as co-director of the Tau Consortium and is on the scientific advisory board of Cohen Veterans Bioscience. The remaining authors declare that they have no competing interests.Attached Files
Published - s41598-018-24904-z.pdf
Submitted - 167874.full.pdf
Supplemental Material - 41598_2018_24904_MOESM1_ESM.docx
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Additional details
- PMCID
- PMC5913225
- Eprint ID
- 86129
- Resolver ID
- CaltechAUTHORS:20180430-133533074
- Alzheimer's Association
- QB3/Calico Longevity Fellowship
- National Defense Science and Engineering Graduate (NDSEG) Fellowship
- 5T32 GM007616-38
- NIH Predoctoral Fellowship
- R01 GM093627
- NIH
- DP2 GM119139
- NIH
- Paul G. Allen Family Foundation
- U54 NS100717
- NIH
- Tau Consortium
- Chan-Zuckerberg Biohub
- Paul F. Glenn Center for Aging Research
- Created
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2018-04-30Created from EPrint's datestamp field
- Updated
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2022-03-11Created from EPrint's last_modified field