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Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy

Microtubule-associated protein tau (MAPT) aggregates in neurons, astrocytes and oligodendrocytes in a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is a target of therapy and the strategy includes either the elimination of pathological tau aggregates or re...

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Autores principales: Forrest, Shelley L., Lee, Seojin, Nassir, Nasna, Martinez-Valbuena, Ivan, Sackmann, Valerie, Li, Jun, Ahmed, Awab, Tartaglia, Maria Carmela, Ittner, Lars M., Lang, Anthony E., Uddin, Mohammed, Kovacs, Gabor G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412651/
https://www.ncbi.nlm.nih.gov/pubmed/37354322
http://dx.doi.org/10.1007/s00401-023-02604-x
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author Forrest, Shelley L.
Lee, Seojin
Nassir, Nasna
Martinez-Valbuena, Ivan
Sackmann, Valerie
Li, Jun
Ahmed, Awab
Tartaglia, Maria Carmela
Ittner, Lars M.
Lang, Anthony E.
Uddin, Mohammed
Kovacs, Gabor G.
author_facet Forrest, Shelley L.
Lee, Seojin
Nassir, Nasna
Martinez-Valbuena, Ivan
Sackmann, Valerie
Li, Jun
Ahmed, Awab
Tartaglia, Maria Carmela
Ittner, Lars M.
Lang, Anthony E.
Uddin, Mohammed
Kovacs, Gabor G.
author_sort Forrest, Shelley L.
collection PubMed
description Microtubule-associated protein tau (MAPT) aggregates in neurons, astrocytes and oligodendrocytes in a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is a target of therapy and the strategy includes either the elimination of pathological tau aggregates or reducing MAPT expression, and thus the amount of tau protein made to prevent its aggregation. Disease-associated tau affects brain regions in a sequential manner that includes cell-to-cell spreading. Involvement of glial cells that show tau aggregates is interpreted as glial cells taking up misfolded tau assuming that glial cells do not express enough MAPT. Although studies have evaluated MAPT expression in human brain tissue homogenates, it is not clear whether MAPT expression is compromised in cells accumulating pathological tau. To address these perplexing aspects of disease pathogenesis, this study used RNAscope combined with immunofluorescence (AT8), and single-nuclear(sn) RNAseq to systematically map and quantify MAPT expression dynamics across different cell types and brain regions in controls (n = 3) and evaluated whether tau cytopathology affects MAPT expression in PSP (n = 3). MAPT transcripts were detected in neurons, astrocytes and oligodendrocytes, and varied between brain regions and within each cell type, and were preserved in all cell types with tau aggregates in PSP. These results propose a complex scenario in all cell types, where, in addition to the ingested misfolded tau, the preserved cellular MAPT expression provides a pool for local protein production that can (1) be phosphorylated and aggregated, or (2) feed the seeding of ingested misfolded tau by providing physiological tau, both accentuating the pathological process. Since tau cytopathology does not compromise MAPT gene expression in PSP, a complete loss of tau protein expression as an early pathogenic component is less likely. These observations provide rationale for a dual approach to therapy by decreasing cellular MAPT expression and targeting removal of misfolded tau. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02604-x.
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spelling pubmed-104126512023-08-11 Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy Forrest, Shelley L. Lee, Seojin Nassir, Nasna Martinez-Valbuena, Ivan Sackmann, Valerie Li, Jun Ahmed, Awab Tartaglia, Maria Carmela Ittner, Lars M. Lang, Anthony E. Uddin, Mohammed Kovacs, Gabor G. Acta Neuropathol Original Paper Microtubule-associated protein tau (MAPT) aggregates in neurons, astrocytes and oligodendrocytes in a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is a target of therapy and the strategy includes either the elimination of pathological tau aggregates or reducing MAPT expression, and thus the amount of tau protein made to prevent its aggregation. Disease-associated tau affects brain regions in a sequential manner that includes cell-to-cell spreading. Involvement of glial cells that show tau aggregates is interpreted as glial cells taking up misfolded tau assuming that glial cells do not express enough MAPT. Although studies have evaluated MAPT expression in human brain tissue homogenates, it is not clear whether MAPT expression is compromised in cells accumulating pathological tau. To address these perplexing aspects of disease pathogenesis, this study used RNAscope combined with immunofluorescence (AT8), and single-nuclear(sn) RNAseq to systematically map and quantify MAPT expression dynamics across different cell types and brain regions in controls (n = 3) and evaluated whether tau cytopathology affects MAPT expression in PSP (n = 3). MAPT transcripts were detected in neurons, astrocytes and oligodendrocytes, and varied between brain regions and within each cell type, and were preserved in all cell types with tau aggregates in PSP. These results propose a complex scenario in all cell types, where, in addition to the ingested misfolded tau, the preserved cellular MAPT expression provides a pool for local protein production that can (1) be phosphorylated and aggregated, or (2) feed the seeding of ingested misfolded tau by providing physiological tau, both accentuating the pathological process. Since tau cytopathology does not compromise MAPT gene expression in PSP, a complete loss of tau protein expression as an early pathogenic component is less likely. These observations provide rationale for a dual approach to therapy by decreasing cellular MAPT expression and targeting removal of misfolded tau. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02604-x. Springer Berlin Heidelberg 2023-06-24 2023 /pmc/articles/PMC10412651/ /pubmed/37354322 http://dx.doi.org/10.1007/s00401-023-02604-x 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/) .
spellingShingle Original Paper
Forrest, Shelley L.
Lee, Seojin
Nassir, Nasna
Martinez-Valbuena, Ivan
Sackmann, Valerie
Li, Jun
Ahmed, Awab
Tartaglia, Maria Carmela
Ittner, Lars M.
Lang, Anthony E.
Uddin, Mohammed
Kovacs, Gabor G.
Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy
title Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy
title_full Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy
title_fullStr Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy
title_full_unstemmed Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy
title_short Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy
title_sort cell-specific mapt gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412651/
https://www.ncbi.nlm.nih.gov/pubmed/37354322
http://dx.doi.org/10.1007/s00401-023-02604-x
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