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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Brodsky, Frances M. Kfoury, Najla Li, Mei Yanamandra, Kiran Ouidja, Mohand O. Holmes, Brandon B. Devos, Sarah L. Miller, Timothy M. Papy-garcia, Dulce Marasa, Jayne Bagchi, Devika P. Diamond, Marc I. Kotzbauer, Paul T. Jacks, Rachel |
| Description | Author Affiliation: Holmes BB ( Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 33 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Amyloid Metabolism Heparan Sulfate Proteoglycans Neural Stem Cells Pinocytosis Physiology Tau Proteins Actins Animals Flow Cytometry Fluorescence Resonance Energy Transfer HEK293 Cells Immunohistochemistry Indoles Mice Mice, Inbred C57BL Microscopy, Fluorescence Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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