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Sci Rep. 2018 Apr 23;8(1):6382. doi: 10.1038/s41598-018-24904-z.

Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs).

Author information

1
Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, CA, 93106, USA.
2
Institute for Neurodegenerative Diseases, Department of Biochemistry & Biophysics, The California Institute for Quantitative Biomedical Research, Quantitative Biosciences Institute, University of California, San Francisco, and Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA.
3
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
4
Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, CA, 93106, USA. kenneth.kosik@lifesci.ucsb.edu.

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.

PMID:
29686391
PMCID:
PMC5913225
DOI:
10.1038/s41598-018-24904-z
[Indexed for MEDLINE]
Free PMC Article

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