PT  - JOURNAL ARTICLE
AU  - Jennifer N. Rauch
AU  - John J. Chen
AU  - Alexander W. Sorum
AU  - Gregory M. Miller
AU  - Tal Sharf
AU  - Stephanie K. See
AU  - Linda C. Hsieh-Wilson
AU  - Martin Kampmann
AU  - Kenneth S. Kosik
TI  - Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs)
AID  - 10.1101/167874
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 167874
4099  - http://biorxiv.org/content/early/2017/07/24/167874.short
4100  - http://biorxiv.org/content/early/2017/07/24/167874.full
AB  - 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 tauheparan sulfate interactions and that this modification regulates uptake in human central nervous system cell lines, iPS-derived neurons, and mouse organotypic brain slice culture. Together, these results suggest novel strategies to halt tau transmission.