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NAT10 inhibition corrects nuclear defects in tau mutant human neurons and extends lifespan in a <i>Drosophila</i> tauopathy model.

Overview

Authors: Francesco Paonessa1,2, Bernardo Delarue Bizzini3,4,5, Tom Campbell2, Emily Coode2, Jonathan Lam6, Ravi Solanki1, Richard Butler2,3, James Smith2, Catherine M. Davidson3,4, Delphine Larrieu7, Andrea H. Brand3,4,5, Frederick J. Livesey1,2
ORCID iDs: James Smith, Frederick J. Livesey
  1. Zayed Centre for Rare Disease, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
  2. Talisman Therapeutics, Babraham Research Campus, Cambridge CB22 3AT, UK
  3. The Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK
  4. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK
  5. Department of Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA
  6. Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
  7. Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK
Institutions: University College London (United Kingdom); University of Cambridge (United Kingdom); The Gurdon Institute (United Kingdom); New York University (United States)
Journal: iScience, volume 29, issue 8, article 116861
Dates: received 19 October 2024; accepted 3 July 2026; published online 22 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.isci.2026.116861 · PMID 42540688 · PMCID PMC13426208 · OpenAlex W7170080832
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: human (organism), drosophila (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: Alzheimer’s, dementia, tau protein, human iPSCs, MAPT, Drosophila, neurodegeneration
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: Gurdon Institute; UCL; Talisman; Wellcome Trust Senior Investigator (WT101052MA, 103792); Alzheimer’s Research UK; Stem Cell Research Centre; Great Ormond Street Children’s Charity; Wellcome Trust Investigator (223111); Royal Society Darwin Trust Research (RSRP\R\210002); Wellcome Trust (092096); Cancer Research UK (C6946/A14492); Sir Henry Dale Fellowship; Royal Society (The Royal Society) (206242/Z/17/Z)
Citations: not cited yet (Europe PMC); 41 references in the paper
Research resources: Anti-total tau; rabbit polyclonal RRID:AB_10013724, Normal Rabbit IgG RRID:AB_1031062, Anti-Cofilin (D3F9) XP rabbit monoclonal RRID:AB_10622000, Alexa Fluor 647 donkey anti-mouse RRID:AB_162542, Anti-MAP2 chicken polyclonal RRID:AB_2138153, Anti-NAT10 Polyclonal antibody RRID:AB_2148944, RRID:AB_223647, RRID:AB_223651, Anti-β3-tubulin; mouse monoclonal RRID:AB_2313773, RRID:AB_2533073, RRID:AB_2533741, Alexa Fluor 488 Goat anti-Mouse RRID:AB_2534062, Alexa Fluor 488 donkey anti-rabbit RRID:AB_2535792, Anti-GEF H1 antibody RRID:AB_2549686, Alexa Fluor 568 donkey anti-chicken RRID:AB_2921072, Anti-Kif2a antibody RRID:AB_2921234, Anti-α-tubulin RRID:AB_301787, Anti-Lamin A/C mouse monoclonal (mab636) RRID:AB_325377, Anti-LaminB1; rabbit polyclonal RRID:AB_443298, Anti-β-actin; mouse monoclonal RRID:AB_476697, RRID:AB_528336, S-tdTomato RRID:Addgene_112579, RRID:BDSC_11474, w[∗]; P{w[+mC] = GAL4-elav.L}CG16779[3] RRID:BDSC_8760, Fiji RRID:SCR_002285, Prism 10 RRID:SCR_002798, Mascot RRID:SCR_014322

Abstract

Mutations in the gene encoding the microtubule-associated protein tau (MAPT) that are causal for frontotemporal dementia result in nuclear envelope deformation and disrupted nucleocytoplasmic transport when expressed in human neurons. A small-molecule inhibitor of the acetyltransferase NAT10 has been shown to correct similar nuclear membrane defects in Hutchinson-Gilford progeria syndrome, primarily by modulating microtubule dynamics. We report here that NAT10 inhibition and loss of function correct nuclear membrane abnormalities in human MAPT-mutant neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespan in vivo in a Drosophila model of tauopathy. NAT10 inhibition changes microtubule dynamics and corrects aberrant nucleocytoplasmic transport, and NAT10 directly interacts with regulators of microtubule dynamics in human MAPT-mutant neurons. We conclude that NAT10 mediates neuronal pathologies in tauopathies and is a potential therapeutic target in these diseases.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

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Data

No dataset and no data link were found in the paper.

Data and code availability

• Data reported in this paper will be shared by the lead contact upon request. • The study in this article does not report original code. • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Frederick J. Livesey (0000-0001-6128-3372); removed Frederick J. Livesey

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 7 keywords, 13 funders, 41 references, 27 RRIDs.

Cite

This paper

Paonessa, F., Bizzini, B. D., Campbell, T., Coode, E., Lam, J., Solanki, R., Butler, R., Smith, J., Davidson, C. M., Larrieu, D., Brand, A. H., & Livesey, F. J. (2026). NAT10 inhibition corrects nuclear defects in tau mutant human neurons and extends lifespan in a <i>Drosophila</i> tauopathy model. iScience, 29(8), 116861. https://doi.org/10.1016/j.isci.2026.116861

BibTeX

@article{paonessa2026nat10,
author = {Paonessa, Francesco and Bizzini, Bernardo Delarue and Campbell, Tom and Coode, Emily and Lam, Jonathan and Solanki, Ravi and Butler, Richard and Smith, James and Davidson, Catherine M. and Larrieu, Delphine and Brand, Andrea H. and Livesey, Frederick J.},
title = {{NAT10 inhibition corrects nuclear defects in tau mutant human neurons and extends lifespan in a \<i\>Drosophila\</i\> tauopathy model}},
journal = {iScience},
year = {2026},
month = jul,
volume = {29},
number = {8},
pages = {116861},
publisher = {Elsevier},
issn = {2589-0042},
doi = {10.1016/j.isci.2026.116861},
url = {https://doi.org/10.1016/j.isci.2026.116861},
pmid = {42540688},
pmcid = {PMC13426208}
}

RIS

TY - JOUR
AU - Paonessa, Francesco
AU - Bizzini, Bernardo Delarue
AU - Campbell, Tom
AU - Coode, Emily
AU - Lam, Jonathan
AU - Solanki, Ravi
AU - Butler, Richard
AU - Smith, James
AU - Davidson, Catherine M.
AU - Larrieu, Delphine
AU - Brand, Andrea H.
AU - Livesey, Frederick J.
TI - NAT10 inhibition corrects nuclear defects in tau mutant human neurons and extends lifespan in a <i>Drosophila</i> tauopathy model
T2 - iScience
J2 - iScience
PY - 2026
DA - 2026/07/22
VL - 29
IS - 8
SP - 116861
SN - 2589-0042
PB - Elsevier
DO - 10.1016/j.isci.2026.116861
UR - https://doi.org/10.1016/j.isci.2026.116861
LA - en
ER -

CSL-JSON

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