Contribution of syndecans to cellular uptake and fibrillation of alpha-synuclein and tau

Hudák, Anett and Kusz, Erzsébet and Domonkos, Ildikó and Jósvay, Katalin and Kodamullil, Alpha Tom and Szilák, László and Letoha, Tamás (2019) Contribution of syndecans to cellular uptake and fibrillation of alpha-synuclein and tau. SCIENTIFIC REPORTS, 9. pp. 1-19. ISSN 2045-2322

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Abstract

Scientific evidence suggests that alpha-synuclein and tau have prion-like properties and that prionlike 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 alpha-synuclein and tau has not been explored yet. Here we report that members of the syndecan family of HSPGs mediate cellular uptake of alpha-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 alpha-synuclein and tau. Syndecan-mediated internalization of alpha-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 alpha-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 alpha-synuclein and tau and reveal how syndecans contribute to fundamental molecular events of a-synuclein and tau pathology.

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