Faculty Opinions recommendation of Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds.
Year: 2013
Type: peer-review
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 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. PMID: 23898162 Funding information This work was supported by: NIGMS NIH HHS, United States Grant ID: 1R01GM038093 NINDS NIH HHS, United States Grant ID: K08 NS074194 NCI NIH HHS, United States Grant ID: P50 CA94056 NCI NIH HHS, United States Grant ID: P30 CA091842 NINDS NIH HHS, United States Grant ID: F31 NS079039 NINDS NIH HHS, United States Grant ID: 1R01NS071835 NINDS NIH HHS, United States Grant ID: 1F31NS079039 NINDS NIH HHS, United States Grant ID: R01 NS071835 NIGMS NIH HHS, United States Grant ID: R01 GM038093 NINDS NIH HHS, United States Grant ID: K08NS074194 NINDS NIH HHS, United States Grant ID: P30 NS057105 NCI NIH HHS, United States Grant ID: P50 CA094056 More Less keyboard_arrow_down
Author: John Lazo
Institution: University of Virginia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Health Assistance Foundation, Ruth K. Broad Biomedical Research Foundation, Muscular Dystrophy Association, Alvin J. Siteman Cancer Center, Hope Center for Neurological Disorders, National Institutes of Health, Tau Consortium, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: G1389837536, G1820417268, G1957546282, Tracking the Propagation of Misfolded Tau: A Study of Cellular Uptake and Traffic, WU-MDACC Inter-Institutional Molecular Imaging Center, G486315402, Changing tau Protein Levels and tau Protein Isoforms in Mouse Models of Dementia, G6120206497, CELL-CELL TRANSFER AND PROPAGATION OF TAU AGGREGATES, G9000006824, G9000032081, G9000123772, G9000282729, Cancer Center Support Grant
OpenAlex ID: W4206358938