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Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98

Tau is a neuronal protein that stabilizes axonal microtubules (MTs) in the central nervous system. In Alzheimer’s disease (AD) and other tauopathies, phosphorylated Tau accumulates in intracellular aggregates, a pathological hallmark of these diseases. However, the chronological order of pathologica...

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Autores principales: Diez, Lisa, Kapinos, Larisa E., Hochmair, Janine, Huebschmann, Sabrina, Dominguez-Baquero, Alvaro, Vogt, Amelie, Rankovic, Marija, Zweckstetter, Markus, Lim, Roderick Y. H., Wegmann, Susanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998617/
https://www.ncbi.nlm.nih.gov/pubmed/35408855
http://dx.doi.org/10.3390/ijms23073495
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author Diez, Lisa
Kapinos, Larisa E.
Hochmair, Janine
Huebschmann, Sabrina
Dominguez-Baquero, Alvaro
Vogt, Amelie
Rankovic, Marija
Zweckstetter, Markus
Lim, Roderick Y. H.
Wegmann, Susanne
author_facet Diez, Lisa
Kapinos, Larisa E.
Hochmair, Janine
Huebschmann, Sabrina
Dominguez-Baquero, Alvaro
Vogt, Amelie
Rankovic, Marija
Zweckstetter, Markus
Lim, Roderick Y. H.
Wegmann, Susanne
author_sort Diez, Lisa
collection PubMed
description Tau is a neuronal protein that stabilizes axonal microtubules (MTs) in the central nervous system. In Alzheimer’s disease (AD) and other tauopathies, phosphorylated Tau accumulates in intracellular aggregates, a pathological hallmark of these diseases. However, the chronological order of pathological changes in Tau prior to its cytosolic aggregation remains unresolved. These include its phosphorylation and detachment from MTs, mislocalization into the somatodendritic compartment, and oligomerization in the cytosol. Recently, we showed that Tau can interact with phenylalanine-glycine (FG)-rich nucleoporins (Nups), including Nup98, that form a diffusion barrier inside nuclear pore complexes (NPCs), leading to defects in nucleocytoplasmic transport. Here, we used surface plasmon resonance (SPR) and bio-layer interferometry (BLI) to investigate the molecular details of Tau:Nup98 interactions and determined how Tau phosphorylation and oligomerization impact the interactions. Importantly, phosphorylation, but not acetylation, strongly facilitates the accumulation of Tau with Nup98. Oligomerization, however, seems to inhibit Tau:Nup98 interactions, suggesting that Tau-FG Nup interactions occur prior to oligomerization. Overall, these results provide fundamental insights into the molecular mechanisms of Tau-FG Nup interactions within NPCs, which might explain how stress-and disease-associated posttranslational modifications (PTMs) may lead to Tau-induced nucleocytoplasmic transport (NCT) failure. Intervention strategies that could rescue Tau-induced NCT failure in AD and tauopathies will be further discussed.
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spelling pubmed-89986172022-04-12 Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98 Diez, Lisa Kapinos, Larisa E. Hochmair, Janine Huebschmann, Sabrina Dominguez-Baquero, Alvaro Vogt, Amelie Rankovic, Marija Zweckstetter, Markus Lim, Roderick Y. H. Wegmann, Susanne Int J Mol Sci Article Tau is a neuronal protein that stabilizes axonal microtubules (MTs) in the central nervous system. In Alzheimer’s disease (AD) and other tauopathies, phosphorylated Tau accumulates in intracellular aggregates, a pathological hallmark of these diseases. However, the chronological order of pathological changes in Tau prior to its cytosolic aggregation remains unresolved. These include its phosphorylation and detachment from MTs, mislocalization into the somatodendritic compartment, and oligomerization in the cytosol. Recently, we showed that Tau can interact with phenylalanine-glycine (FG)-rich nucleoporins (Nups), including Nup98, that form a diffusion barrier inside nuclear pore complexes (NPCs), leading to defects in nucleocytoplasmic transport. Here, we used surface plasmon resonance (SPR) and bio-layer interferometry (BLI) to investigate the molecular details of Tau:Nup98 interactions and determined how Tau phosphorylation and oligomerization impact the interactions. Importantly, phosphorylation, but not acetylation, strongly facilitates the accumulation of Tau with Nup98. Oligomerization, however, seems to inhibit Tau:Nup98 interactions, suggesting that Tau-FG Nup interactions occur prior to oligomerization. Overall, these results provide fundamental insights into the molecular mechanisms of Tau-FG Nup interactions within NPCs, which might explain how stress-and disease-associated posttranslational modifications (PTMs) may lead to Tau-induced nucleocytoplasmic transport (NCT) failure. Intervention strategies that could rescue Tau-induced NCT failure in AD and tauopathies will be further discussed. MDPI 2022-03-23 /pmc/articles/PMC8998617/ /pubmed/35408855 http://dx.doi.org/10.3390/ijms23073495 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Diez, Lisa
Kapinos, Larisa E.
Hochmair, Janine
Huebschmann, Sabrina
Dominguez-Baquero, Alvaro
Vogt, Amelie
Rankovic, Marija
Zweckstetter, Markus
Lim, Roderick Y. H.
Wegmann, Susanne
Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98
title Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98
title_full Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98
title_fullStr Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98
title_full_unstemmed Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98
title_short Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98
title_sort phosphorylation but not oligomerization drives the accumulation of tau with nucleoporin nup98
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998617/
https://www.ncbi.nlm.nih.gov/pubmed/35408855
http://dx.doi.org/10.3390/ijms23073495
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