Fully co-factor-free ClearTau platform produces seeding-competent Tau fibrils for reconstructing pathological Tau aggregates.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 07 2023
04 07 2023
Historique:
received:
13
04
2022
accepted:
06
06
2023
medline:
6
7
2023
pubmed:
5
7
2023
entrez:
4
7
2023
Statut:
epublish
Résumé
Tau protein fibrillization is implicated in the pathogenesis of several neurodegenerative diseases collectively known as Tauopathies. For decades, investigating Tau fibrillization in vitro has required the addition of polyanions or other co-factors to induce its misfolding and aggregation, with heparin being the most commonly used. However, heparin-induced Tau fibrils exhibit high morphological heterogeneity and a striking structural divergence from Tau fibrils isolated from Tauopathies patients' brains at ultra- and macro-structural levels. To address these limitations, we developed a quick, cheap, and effective method for producing completely co-factor-free fibrils from all full-length Tau isoforms and mixtures thereof. We show that Tau fibrils generated using this ClearTau method - ClearTau fibrils - exhibit amyloid-like features, possess seeding activity in biosensor cells and hiPSC-derived neurons, retain RNA-binding capacity, and have morphological properties and structures more reminiscent of the properties of the brain-derived Tau fibrils. We present the proof-of-concept implementation of the ClearTau platform for screening Tau aggregation-modifying compounds. We demonstrate that these advances open opportunities to investigate the pathophysiology of disease-relevant Tau aggregates and will facilitate the development of Tau pathology-targeting and modifying therapies and PET tracers that can distinguish between different Tauopathies.
Identifiants
pubmed: 37402718
doi: 10.1038/s41467-023-39314-7
pii: 10.1038/s41467-023-39314-7
pmc: PMC10319797
doi:
Substances chimiques
tau Proteins
0
Heparin
9005-49-6
Protein Isoforms
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3939Informations de copyright
© 2023. The Author(s).
Références
J Exp Med. 2016 Nov 14;213(12):2635-2654
pubmed: 27810929
Ann Neurol. 1997 Feb;41(2):200-9
pubmed: 9029069
Nat Struct Mol Biol. 2008 Jun;15(6):558-66
pubmed: 18511942
J Biol Chem. 2021 Jan-Jun;296:100788
pubmed: 34019875
J Biol Chem. 1988 Apr 25;263(12):5876-83
pubmed: 2833519
J Struct Biol. 2005 Oct;152(1):36-51
pubmed: 16182563
Microsc Res Tech. 2014 Feb;77(2):133-7
pubmed: 24258797
Biochemistry. 2021 Nov 30;60(47):3644-3658
pubmed: 34730940
J Biol Chem. 2007 Feb 23;282(8):5862-70
pubmed: 17189262
J Am Chem Soc. 2018 May 30;140(21):6611-6621
pubmed: 29684271
Mol Pharm. 2018 Jun 4;15(6):2098-2106
pubmed: 29709194
Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4376-85
pubmed: 25261551
iScience. 2021 Dec 18;25(1):103658
pubmed: 35072001
J Biol Chem. 2020 Jun 5;295(23):7905-7922
pubmed: 32341125
Nat Commun. 2022 May 27;13(1):2967
pubmed: 35624093
Trends Cell Biol. 2022 Jul;32(7):611-623
pubmed: 35181198
Biochemistry. 2000 Sep 26;39(38):11714-21
pubmed: 10995239
Mol Neurodegener. 2022 Mar 5;17(1):18
pubmed: 35248124
Curr Opin Chem Biol. 2015 Oct;28:115-22
pubmed: 26196731
Annu Rev Neurosci. 2001;24:1121-59
pubmed: 11520930
Neuroreport. 2002 Oct 28;13(15):1913-6
pubmed: 12395090
Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2119952119
pubmed: 35377792
J Mol Biol. 2018 Oct 19;430(21):4119-4131
pubmed: 30121297
Cell Prolif. 2010 Feb;43(1):9-18
pubmed: 19845689
Alzheimers Res Ther. 2014 Jan 02;6(1):1
pubmed: 24382028
Bioeng Transl Med. 2021 Jun 01;6(3):e10231
pubmed: 34589603
Nat Methods. 2017 Mar;14(3):290-296
pubmed: 28165473
Methods Mol Biol. 2017;1523:349-359
pubmed: 27975263
Elife. 2022 Mar 04;11:
pubmed: 35244536
Antioxid Redox Signal. 2013 Mar 1;18(7):770-83
pubmed: 22867050
Protein Sci. 2019 Feb;28(2):382-402
pubmed: 30394624
FEBS Lett. 1996 Dec 16;399(3):344-9
pubmed: 8985176
Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):13234-13239
pubmed: 30538196
J Struct Biol. 2017 May;198(2):124-133
pubmed: 28344036
J Cell Biol. 1986 Dec;103(6 Pt 2):2739-46
pubmed: 3098742
Nat Commun. 2021 Jul 9;12(1):4231
pubmed: 34244499
Nature. 2021 Oct;598(7880):359-363
pubmed: 34588692
Elife. 2019 Feb 05;8:
pubmed: 30720432
Biochem Soc Trans. 2006 Jun;34(Pt 3):458-60
pubmed: 16709187
J Vis Exp. 2015 Dec 08;(106):e53205
pubmed: 26710240
FEBS Lett. 1995 Sep 18;372(1):65-8
pubmed: 7556645
J Am Chem Soc. 2023 Feb 8;:
pubmed: 36753572
J Biol Chem. 2006 Jul 14;281(28):19107-14
pubmed: 16687396
Biochem Biophys Res Commun. 1984 May 16;120(3):885-90
pubmed: 6375662
Circ Res. 1997 Jul;81(1):17-23
pubmed: 9201023
J Biol Chem. 2018 Jul 6;293(27):10826-10840
pubmed: 29752409
Nat Rev Dis Primers. 2015 Oct 15;1:15056
pubmed: 27188934
Thromb Haemost. 2013 Jun;109(6):1148-57
pubmed: 23571852
Chem Soc Rev. 2022 Jan 24;51(2):513-565
pubmed: 34889934
Int J Biol Macromol. 2019 Jul 15;133:473-483
pubmed: 31004638
Acta Neuropathol. 1998 Nov;96(5):487-94
pubmed: 9829812
J Cell Sci. 2004 Dec 1;117(Pt 25):6129-41
pubmed: 15564376
Nature. 1998 Jun 18;393(6686):702-5
pubmed: 9641683
Thromb Haemost. 2016 Oct 28;116(5):792-798
pubmed: 27465274
J Biol Chem. 2019 Jun 14;294(24):9316-9325
pubmed: 31088912
Mol Hum Reprod. 2006 Apr;12(4):237-43
pubmed: 16556679
Science. 2008 Feb 22;319(5866):1086-9
pubmed: 18202255
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11213-8
pubmed: 8855335
J Neurol Sci. 1970 Sep;11(3):205-42
pubmed: 5505685
Angew Chem Int Ed Engl. 2020 Mar 2;59(10):4059-4067
pubmed: 31863676
Biomolecules. 2020 Jun 18;10(6):
pubmed: 32570820
Biochimie. 1984 Apr;66(4):305-11
pubmed: 6743699
Biochemistry. 2006 Oct 17;45(41):12560-72
pubmed: 17029411
Curr Top Med Chem. 2008;8(2):80-100
pubmed: 18289079
Nature. 1963 Jan 12;197:192-3
pubmed: 14032480
Methods Mol Biol. 2018;1779:73-83
pubmed: 29886528
Neurobiol Dis. 2021 Dec;161:105536
pubmed: 34718129
Nature. 1996 Oct 10;383(6600):550-3
pubmed: 8849730
J Biol Chem. 2020 Mar 6;295(10):2974-2983
pubmed: 31974166