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Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau

Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer’s disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical resi...

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Autores principales: Smith, Ethan D., Vo, Quan, Giasson, Benoit I., Borchelt, David R., Prokop, Stefan, Chakrabarty, Paramita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10612232/
https://www.ncbi.nlm.nih.gov/pubmed/37891635
http://dx.doi.org/10.1186/s40478-023-01664-0
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author Smith, Ethan D.
Vo, Quan
Giasson, Benoit I.
Borchelt, David R.
Prokop, Stefan
Chakrabarty, Paramita
author_facet Smith, Ethan D.
Vo, Quan
Giasson, Benoit I.
Borchelt, David R.
Prokop, Stefan
Chakrabarty, Paramita
author_sort Smith, Ethan D.
collection PubMed
description Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer’s disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical residues determine templated tau seeding. Our initial data with phosphorylation-ablating mutations (Ser/Thr → Ala) on select sites of P301L tau showed no changes in seeding efficacy by AD-tau or PSP-tau. Interestingly, when specific sites in the R1-R2 repeat domains (Ser262/Thr263/Ser289/Ser305) were mutated to phosphorylation-mimicking amino acid Glu, it substantially reduced the seeding efficiency of AD-tau, but not PSP-tau seeds. The resultant detergent-insoluble tau shows deficient phosphorylation on AT8, AT100, AT180 and PHF1 epitopes, indicating inter-domain cooperativity. We further identify Ser305 as a critical determinant of AD-tau-specific seeding, whereby the phospho-mimicking Ser305Glu tau abrogates seeding by AD-tau but not PSP-tau. This suggests that phosphorylation on Ser305 could be related to the formation of disease-specific tau strains. Our results highlight the existence of a phospho-PTM code in tau seeding and further demonstrate the distinctive nature of this code in 4R tauopathies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01664-0.
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spelling pubmed-106122322023-10-29 Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau Smith, Ethan D. Vo, Quan Giasson, Benoit I. Borchelt, David R. Prokop, Stefan Chakrabarty, Paramita Acta Neuropathol Commun Research Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer’s disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical residues determine templated tau seeding. Our initial data with phosphorylation-ablating mutations (Ser/Thr → Ala) on select sites of P301L tau showed no changes in seeding efficacy by AD-tau or PSP-tau. Interestingly, when specific sites in the R1-R2 repeat domains (Ser262/Thr263/Ser289/Ser305) were mutated to phosphorylation-mimicking amino acid Glu, it substantially reduced the seeding efficiency of AD-tau, but not PSP-tau seeds. The resultant detergent-insoluble tau shows deficient phosphorylation on AT8, AT100, AT180 and PHF1 epitopes, indicating inter-domain cooperativity. We further identify Ser305 as a critical determinant of AD-tau-specific seeding, whereby the phospho-mimicking Ser305Glu tau abrogates seeding by AD-tau but not PSP-tau. This suggests that phosphorylation on Ser305 could be related to the formation of disease-specific tau strains. Our results highlight the existence of a phospho-PTM code in tau seeding and further demonstrate the distinctive nature of this code in 4R tauopathies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01664-0. BioMed Central 2023-10-27 /pmc/articles/PMC10612232/ /pubmed/37891635 http://dx.doi.org/10.1186/s40478-023-01664-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Smith, Ethan D.
Vo, Quan
Giasson, Benoit I.
Borchelt, David R.
Prokop, Stefan
Chakrabarty, Paramita
Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau
title Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau
title_full Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau
title_fullStr Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau
title_full_unstemmed Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau
title_short Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau
title_sort human tauopathy strains defined by phosphorylation in r1-r2 repeat domains of tau
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10612232/
https://www.ncbi.nlm.nih.gov/pubmed/37891635
http://dx.doi.org/10.1186/s40478-023-01664-0
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