The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau
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 Ta...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-10-01
|
| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2021.779240/full |
| _version_ | 1797682351446163456 |
|---|---|
| author | Chen Lyu Stefano Da Vela Youssra Al-Hilaly Karen E. Marshall Richard Thorogate Dmitri Svergun Louise C. Serpell Annalisa Pastore Diane P. Hanger |
| author_facet | Chen Lyu Stefano Da Vela Youssra Al-Hilaly Karen E. Marshall Richard Thorogate Dmitri Svergun Louise C. Serpell Annalisa Pastore Diane P. Hanger |
| author_sort | Chen Lyu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:58:23Z |
| format | Article |
| id | doaj.art-be685484133d4c3a8d3091c5db1f9df6 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-03-11T23:58:23Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-be685484133d4c3a8d3091c5db1f9df62023-09-18T07:03:13ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2021-10-01810.3389/fmolb.2021.779240779240The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length TauChen Lyu0Stefano Da Vela1Youssra Al-Hilaly2Karen E. Marshall3Richard Thorogate4Dmitri Svergun5Louise C. Serpell6Annalisa Pastore7Diane P. Hanger8Department of Basic and Clinical Neuroscience, King’s College London, London, United KingdomEuropean Molecular Biology Laboratory, Hamburg Site, Hamburg, GermanySussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, United KingdomSussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, United KingdomLondon Centre for Nanotechnology, University College London, London, United KingdomEuropean Molecular Biology Laboratory, Hamburg Site, Hamburg, GermanySussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, United KingdomDepartment of Basic and Clinical Neuroscience, King’s College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, King’s College London, London, United KingdomTau35 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.https://www.frontiersin.org/articles/10.3389/fmolb.2021.779240/fullbiophysical studieshybrid methodstauopathytau truncationsmall angle x-ray scatteringintrinsically disordered proteins |
| spellingShingle | Chen Lyu Stefano Da Vela Youssra Al-Hilaly Karen E. Marshall Richard Thorogate Dmitri Svergun Louise C. Serpell Annalisa Pastore Diane P. Hanger The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau Frontiers in Molecular Biosciences biophysical studies hybrid methods tauopathy tau truncation small angle x-ray scattering intrinsically disordered proteins |
| title | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
| title_full | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
| title_fullStr | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
| title_full_unstemmed | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
| title_short | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
| title_sort | disease associated tau35 fragment has an increased propensity to aggregate compared to full length tau |
| topic | biophysical studies hybrid methods tauopathy tau truncation small angle x-ray scattering intrinsically disordered proteins |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2021.779240/full |
| work_keys_str_mv | AT chenlyu thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT stefanodavela thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT youssraalhilaly thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT karenemarshall thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT richardthorogate thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT dmitrisvergun thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT louisecserpell thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT annalisapastore thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT dianephanger thediseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT chenlyu diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT stefanodavela diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT youssraalhilaly diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT karenemarshall diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT richardthorogate diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT dmitrisvergun diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT louisecserpell diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT annalisapastore diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau AT dianephanger diseaseassociatedtau35fragmenthasanincreasedpropensitytoaggregatecomparedtofulllengthtau |