The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau

Frontiers in Molecular Biosciences

Diane P. Hanger¹  Chen Lyu¹  Annalisa Pastore¹  Dmitri Svergun²  Stefano Da Vela²  Richard Thorogate³  Youssra Al-Hilaly⁴  Karen E. Marshall⁴  Louise C. Serpell⁴ 

[1] Department of Basic and Clinical Neuroscience, King’s College London, London, United Kingdom;European Molecular Biology Laboratory, Hamburg Site, Hamburg, Germany;London Centre for Nanotechnology, University College London, London, United Kingdom;Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, United Kingdom;

关键词: biophysical studies;    hybrid methods;    tauopathy;    tau truncation;    small angle x-ray scattering;    intrinsically disordered proteins;   

DOI  :  10.3389/fmolb.2021.779240

来源: DOAJ

【 摘 要 】

Tau35 is a truncated form of tau found in human brain in a subset of tauopathies. Tau35 expression in mice recapitulates key features of human disease, including progressive increase in tau phosphorylation, along with cognitive and motor dysfunction. The appearance of aggregated tau suggests that Tau35 may have structural properties distinct from those of other tau species that could account for its pathological role in disease. To address this hypothesis, we performed a structural characterization of monomeric and aggregated Tau35 and compared the results to those of two longer isoforms, 2N3R and 2N4R tau. We used small angle X-ray scattering to show that Tau35, 2N3R and 2N4R tau all behave as disordered monomeric species but Tau35 exhibits higher rigidity. In the presence of the poly-anion heparin, Tau35 increases thioflavin T fluorescence significantly faster and to a greater extent than full-length tau, demonstrating a higher propensity to aggregate. By using atomic force microscopy, circular dichroism, transmission electron microscopy and X-ray fiber diffraction, we provide evidence that Tau35 aggregation is mechanistically and morphologically similar to previously reported tau fibrils but they are more densely packed. These data increase our understanding of the aggregation inducing properties of clinically relevant tau fragments and their potentially damaging role in the pathogenesis of human tauopathies.

【 授权许可】

Unknown