3-O-Sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake. Academic Article uri icon

Overview

abstract

  • Prion-like transcellular spreading of tau in Alzheimer's Disease (AD) is mediated by tau binding to cell surface heparan sulfate (HS). However, the structural determinants for tau-HS interaction are not well understood. Microarray and SPR assays of structurally defined HS oligosaccharides show that a rare 3-O-sulfation (3-O-S) of HS significantly enhances tau binding. In Hs3st1-/- (HS 3-O-sulfotransferase-1 knockout) cells, reduced 3-O-S levels of HS diminished both cell surface binding and internalization of tau. In a cell culture, the addition of a 3-O-S HS 12-mer reduced both tau cell surface binding and cellular uptake. NMR titrations mapped 3-O-S binding sites to the microtubule binding repeat 2 (R2) and proline-rich region 2 (PRR2) of tau. Tau is only the seventh protein currently known to recognize HS 3-O-sulfation. Our work demonstrates that this rare 3-O-sulfation enhances tau-HS binding and likely the transcellular spread of tau, providing a novel target for disease-modifying treatment of AD and other tauopathies.

publication date

  • December 10, 2019

Research

keywords

  • Alzheimer Disease
  • Cell Membrane
  • Heparitin Sulfate
  • tau Proteins

Identity

PubMed Central ID

  • PMC6982596

Scopus Document Identifier

  • 85076531942

Digital Object Identifier (DOI)

  • 10.1038/s41467-019-10355-1

PubMed ID

  • 31692167

Additional Document Info

volume

  • 59

issue

  • 5