Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds

Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):E3138-47. doi: 10.1073/pnas.1301440110. Epub 2013 Jul 29.


Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregates drives the progression of neurodegenerative diseases in a prion-like manner. This phenomenon is now well described in cell and animal models and involves the release of protein aggregates into the extracellular space. Free aggregates then enter neighboring cells to seed further fibrillization. The mechanism by which aggregated extracellular proteins such as tau and α-synuclein bind and enter cells to trigger intracellular fibril formation is unknown. Prior work indicates that prion protein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface to transmit pathologic processes. Here, we find that tau fibril uptake also occurs via HSPG binding. This is blocked in cultured cells and primary neurons by heparin, chlorate, heparinase, and genetic knockdown of a key HSPG synthetic enzyme, Ext1. Interference with tau binding to HSPGs prevents recombinant tau fibrils from inducing intracellular aggregation and blocks transcellular aggregate propagation. In vivo, a heparin mimetic, F6, blocks neuronal uptake of stereotactically injected tau fibrils. Finally, uptake and seeding by α-synuclein fibrils, but not huntingtin fibrils, occurs by the same mechanism as tau. This work suggests a unifying mechanism of cell uptake and propagation for tauopathy and synucleinopathy.

Keywords: Alzheimer's disease; macropinocytosis; neurodegeneration; prion-like mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amyloid / metabolism*
  • Animals
  • Flow Cytometry
  • Fluorescence Resonance Energy Transfer
  • HEK293 Cells
  • Heparan Sulfate Proteoglycans / metabolism*
  • Humans
  • Immunohistochemistry
  • Indoles
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / physiology
  • Pinocytosis / physiology*
  • tau Proteins / metabolism*


  • Actins
  • Amyloid
  • Heparan Sulfate Proteoglycans
  • Indoles
  • Mapt protein, mouse
  • tau Proteins
  • DAPI