Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds

Brandon B. Holmes, Sarah L. DeVos, Najla Kfoury, Mei Li, Rachel Jacks, Kiran Yanamandra, Mohand O. Ouidja, Frances M. Brodsky, Jayne Marasa, Devika P. Bagchi, Paul T. Kotzbauer, Timothy M. Miller, Dulce Papy-Garcia, Marc I. Diamond

Research output: Contribution to journalArticlepeer-review

374 Scopus citations

Abstract

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 ?-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 ?-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.

Original languageEnglish
Pages (from-to)E3138-E3147
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number33
DOIs
StatePublished - Aug 13 2013

Keywords

  • Alzheimer's disease
  • Macropinocytosis
  • Neurodegeneration
  • Prion-like mechanisms

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