Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds

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.neurodegeneration | Alzheimer's disease | prion-like mechanisms | macropinocytosis

Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

“…Although we have not identified the receptors involved in this process, our previous work on microglia would suggest a large receptor complex involving scavenger or other pattern-recognition receptors and signaling receptors may be participating (27). Heparin sulfate proteoglycans have been shown to be involved in aggregate uptake of tau, alpha-synuclein, and prion protein (28,29), and it is interesting to speculate that this family of receptors could be involved here. However, before cell death ensues in ALS or other neurodegenerative diseases, pathology can spread from cell to cell and region to region (8), suggesting another mechanism that may be more relevant to early stages of the disease.…”

Proteopathic tau seeding predicts tauopathy in vivo

“…Our laboratory has previously used FRET to quantify protein aggregation in cultured cells (13,21,22). The use of a plate reader for measuring FRET has certain disadvantages, and thus we created a facile, next-generation system to detect seeding activity with ultrahigh sensitivity and specificity.…”

“…This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections. Our laboratory and others have previously hypothesized that tau aggregates-or seeds-serve as this agent of spread, transmitting the aggregated state from cell to cell via prion-like mechanisms (6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…Tau seeds applied to the outside of cells bind the cell surface by attaching to heparan sulfate proteoglycans, triggering uptake by macropinocytosis (13). Upon internalization, tau seeds nucleate the fibrillization of endogenous tau monomer via templated conformational change, or seeding (8,10).…”

Structural Characterization of Heparin-induced Glyceraldehyde-3-phosphate Dehydrogenase Protofibrils Preventing α-Synuclein Oligomeric Species Toxicity

“…Moreover, genomic analysis suggests that GAPDH has a protective effect on late-onset Alzheimer disease (23). On the other hand, GAGs are present in most, if not all, types of amyloids inside and outside of the cells (24,25). In vitro, GAGs have proved to affect protein aggregation kinetics (26).…”