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Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress

Alzheimer’s disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa F...

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Autores principales: Jiang, Lulu, Chakraborty, Pijush, Zhang, Lushuang, Wong, Melissa, Hill, Shannon E., Webber, Chelsea Joy, Libera, Jenna, Blair, Laura J., Wolozin, Benjamin, Zweckstetter, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891691/
https://www.ncbi.nlm.nih.gov/pubmed/36724228
http://dx.doi.org/10.1126/sciadv.add9789
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author Jiang, Lulu
Chakraborty, Pijush
Zhang, Lushuang
Wong, Melissa
Hill, Shannon E.
Webber, Chelsea Joy
Libera, Jenna
Blair, Laura J.
Wolozin, Benjamin
Zweckstetter, Markus
author_facet Jiang, Lulu
Chakraborty, Pijush
Zhang, Lushuang
Wong, Melissa
Hill, Shannon E.
Webber, Chelsea Joy
Libera, Jenna
Blair, Laura J.
Wolozin, Benjamin
Zweckstetter, Markus
author_sort Jiang, Lulu
collection PubMed
description Alzheimer’s disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance–based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network–based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology.
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spelling pubmed-98916912023-02-08 Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress Jiang, Lulu Chakraborty, Pijush Zhang, Lushuang Wong, Melissa Hill, Shannon E. Webber, Chelsea Joy Libera, Jenna Blair, Laura J. Wolozin, Benjamin Zweckstetter, Markus Sci Adv Neuroscience Alzheimer’s disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance–based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network–based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology. American Association for the Advancement of Science 2023-02-01 /pmc/articles/PMC9891691/ /pubmed/36724228 http://dx.doi.org/10.1126/sciadv.add9789 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Neuroscience
Jiang, Lulu
Chakraborty, Pijush
Zhang, Lushuang
Wong, Melissa
Hill, Shannon E.
Webber, Chelsea Joy
Libera, Jenna
Blair, Laura J.
Wolozin, Benjamin
Zweckstetter, Markus
Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress
title Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress
title_full Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress
title_fullStr Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress
title_full_unstemmed Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress
title_short Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress
title_sort chaperoning of specific tau structure by immunophilin fkbp12 regulates the neuronal resilience to extracellular stress
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891691/
https://www.ncbi.nlm.nih.gov/pubmed/36724228
http://dx.doi.org/10.1126/sciadv.add9789
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