Contribution of syndecans to cellular uptake and fibrillation of \u03b1-synuclein and tau

Anett Hudák,Alpha Tom Kodamullil,Tamás Letoha,Katalin Jósvay,Erzsébet Kusz,Ildikó Domonkos,László Szilák,Martin Hofmann-Apitius

doi:10.1038/s41598-019-53038-z

Abstract

Scientific evidence suggests that α-synuclein and tau have prion-like properties and that prion-like spreading and seeding of misfolded protein aggregates constitutes a central mechanism for neurodegeneration. Heparan sulfate proteoglycans (HSPGs) in the plasma membrane support this process by attaching misfolded protein fibrils. Despite of intense studies, contribution of specific HSPGs to seeding and spreading of α-synuclein and tau has not been explored yet. Here we report that members of the syndecan family of HSPGs mediate cellular uptake of α-synuclein and tau fibrils via a lipid-raft dependent and clathrin-independent endocytic route. Among syndecans, the neuron predominant syndecan-3 exhibits the highest affinity for both α-synuclein and tau. Syndecan-mediated internalization of α-synuclein and tau depends heavily on conformation as uptake via syndecans start to dominate once fibrils are formed. Overexpression of syndecans, on the other hand, reduces cellular uptake of monomeric α-synuclein and tau, yet exerts a fibril forming effect on both proteins. Data obtained from syndecan overexpressing cellular models presents syndecans, especially the neuron predominant syndecan-3, as important mediators of seeding and spreading of α-synuclein and tau and reveal how syndecans contribute to fundamental molecular events of α-synuclein and tau pathology.

Highlights

Scientific evidence suggests that α-synuclein and tau have prion-like properties and that prionlike spreading and seeding of misfolded protein aggregates constitutes a central mechanism for neurodegeneration
Studying the fibrillation and intracellular uptake of amyloid-β(1–42), we found that the overexpression of SDCs, especially the neuron predominant SDC3, markedly supports amyloid-β pathology by triggering fibrillation and intracellular delivery of fibrillar amyloid-β(1–42)[17]
Heparan sulfate proteoglycans (HSPGs) have been already acknowledged as major players in the cellular uptake of α-syn and tau fibrils, evidence on the contribution of specific SDC isoforms to cellular internalization of these misfolded proteins is still waiting to be explored[76]

Summary

Introduction

Scientific evidence suggests that α-synuclein and tau have prion-like properties and that prionlike spreading and seeding of misfolded protein aggregates constitutes a central mechanism for neurodegeneration. Growing scientific data suggest the major role of cell surface heparan sulfate proteoglycans (HSPGs) in cellular attachment and subsequent internalization of α-syn and tau fibrils[13,14,15,16]. These findings highlight the potential effects of HSPGs on cellular pathophysiology driving neurodegeneration. As α-syn and tau have been shown to interact with HSPGs, exploration of these interactions might help scientists to identify viable targets for future therapeutic interventions against neurodegeneration[13,14] These interactions involve proteoglycans’ HS chains defined by their sulfation patterns[20]. Studying the fibrillation and intracellular uptake of amyloid-β(1–42), we found that the overexpression of SDCs, especially the neuron predominant SDC3, markedly supports amyloid-β pathology by triggering fibrillation and intracellular delivery of fibrillar amyloid-β(1–42)[17]

Methods

Results

Conclusion