OSCR

HDAC6 inhibition alleviates mitochondrial trafficking in models of Charcot-Marie-Tooth disease type 2A.

Overview

Authors: Lydia H Jestice1,2, Larissa Butler1,2, Rebecca A Lea1,2, Kathryn I Adamson2,3,4, Jonas Van Lent5,6, Stuart L Johnson1,2, Hollie Weedon1,2, Eldriena D’Silva1,2, Gabriele Gelezauskaite1,2, Bob Asselbergh7,8, Eloise Brown2,3, Owen Laing1,2, Christopher J Price1,2, Dylan Stavish1,2, Anestis Tsakiridis1,2, Mark O Collins1,2, Vincent Timmerman5,6, Kurt J De Vos2,3, Alison E Twelvetrees2,3, Andrew J Grierson2,3,4, Ivana Barbaric1,2
ORCID iDs: Eloise Brown, Mark O Collins, Vincent Timmerman, Andrew J Grierson
  1. School of Biosciences
  2. Neuroscience Institute
  3. Sheffield Institute for Translational Neuroscience, and
  4. Bateson Centre, The University of Sheffield, Sheffield, United Kingdom
  5. Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
  6. Laboratory of Neuromuscular Pathology, Institute Born Bunge, Antwerp, Belgium
  7. VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
  8. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
Institutions: Neuroscience Institute (Italy); University of Sheffield (United Kingdom); University of Antwerp (Belgium); Institute Born-Bunge (Belgium); VIB-UAntwerp Center for Molecular Neurology (Belgium)
Journal: JCI insight, volume 11, issue 16, article e200106
Dates: received 30 September 2025; accepted 7 July 2026; published online 14 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1172/jci.insight.200106 · PMID 42446926 · PMCID PMC13502185 · OpenAlex W7168237746
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), zebrafish (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials, Connectivity
Keywords: Cell biology, Neuroscience, Neuromuscular disease
MeSH: Charcot-Marie-Tooth Disease*, Histone Deacetylase 6*, Histone Deacetylase Inhibitors*, Mitochondria*, Animals, Axons, Disease Models, Animal, GTP Phosphohydrolases, Human Embryonic Stem Cells, Humans, Mitochondrial Proteins, Motor Neurons, Zebrafish (* major topic)
Topic: Hereditary Neurological Disorders (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: Alzheimer's Society (AS-PG-15-023); Wellcome Trust (220192/Z/20/Z)
Citations: not cited yet (Europe PMC); 64 references in the paper
Research resources: RRID:CVCL_BW83, MFN2+/+ WT2 clone RRID:CVCL_E3QK, MFN2R94Q/+ Het1 RRID:CVCL_E3QL, MFN2R94Q/+ Het3.1 RRID:CVCL_E3QM, MFN2R94Q/+ Het3.2 RRID:CVCL_E3QN, MFN2R94Q/+ Het4 RRID:CVCL_E3QP

Abstract

Charcot-Marie-Tooth disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain, and loss of sensation in limbs. CMT type 2A (CMT2A) is the most common form of axonal CMT and is associated with a more severe clinical manifestation. However, there are no treatments currently available. To investigate disease mechanisms and facilitate treatment discovery, we developed an in vitro model for CMT2A by introducing the patient-specific MFN2R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant and wild-type hESCs differentiated into spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in altered distribution of mitochondria in axons. Unbiased quantitative proteomic profiling of the endogenous MFN2 interactome revealed dose-dependent remodelling by the R94Q variant across 412 proteins, highlighting candidate mechanisms in disease pathology. Importantly, we showed that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor. Chemical inhibition of HDAC6 also rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a variant-specific insight into CMT2A disease mechanisms and confirms HDAC6 as a promising target for further therapeutic development.

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

Code

The paper links to its data, not to its authors' code: see the Data section.

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

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Data

Datasets cited

Data availability

Code that was used to analyze Kymobutler outputs is deposited in ORDA (https://doi.org/10.15131/shef.data.30196639.v1), the University of Sheffield data repository, powered by Figshare.

The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD077751.

Values for all data points in graphs are reported in the Supporting Data Values file.

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 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 21 authors, 3 keywords, 13 MeSH terms, 2 funders, 62 references, 6 RRIDs.

Cite

This paper

Jestice, L. H., Butler, L., Lea, R. A., Adamson, K. I., Van Lent, J., Johnson, S. L., Weedon, H., D’Silva, E., Gelezauskaite, G., Asselbergh, B., Brown, E., Laing, O., Price, C. J., Stavish, D., Tsakiridis, A., Collins, M. O., Timmerman, V., De Vos, K. J., Twelvetrees, A. E., . . . Barbaric, I. (2026). HDAC6 inhibition alleviates mitochondrial trafficking in models of Charcot-Marie-Tooth disease type 2A. JCI insight, 11(16), e200106. https://doi.org/10.1172/jci.insight.200106

BibTeX

@article{jestice2026hdac6,
author = {Jestice, Lydia H and Butler, Larissa and Lea, Rebecca A and Adamson, Kathryn I and Van Lent, Jonas and Johnson, Stuart L and Weedon, Hollie and D’Silva, Eldriena and Gelezauskaite, Gabriele and Asselbergh, Bob and Brown, Eloise and Laing, Owen and Price, Christopher J and Stavish, Dylan and Tsakiridis, Anestis and Collins, Mark O and Timmerman, Vincent and De Vos, Kurt J and Twelvetrees, Alison E and Grierson, Andrew J and Barbaric, Ivana},
title = {{HDAC6 inhibition alleviates mitochondrial trafficking in models of Charcot-Marie-Tooth disease type 2A}},
journal = {JCI insight},
year = {2026},
month = jul,
volume = {11},
number = {16},
pages = {e200106},
publisher = {American Society for Clinical Investigation},
issn = {2379-3708},
doi = {10.1172/jci.insight.200106},
url = {https://doi.org/10.1172/jci.insight.200106},
pmid = {42446926},
pmcid = {PMC13502185}
}

RIS

TY - JOUR
AU - Jestice, Lydia H
AU - Butler, Larissa
AU - Lea, Rebecca A
AU - Adamson, Kathryn I
AU - Van Lent, Jonas
AU - Johnson, Stuart L
AU - Weedon, Hollie
AU - D’Silva, Eldriena
AU - Gelezauskaite, Gabriele
AU - Asselbergh, Bob
AU - Brown, Eloise
AU - Laing, Owen
AU - Price, Christopher J
AU - Stavish, Dylan
AU - Tsakiridis, Anestis
AU - Collins, Mark O
AU - Timmerman, Vincent
AU - De Vos, Kurt J
AU - Twelvetrees, Alison E
AU - Grierson, Andrew J
AU - Barbaric, Ivana
TI - HDAC6 inhibition alleviates mitochondrial trafficking in models of Charcot-Marie-Tooth disease type 2A
T2 - JCI insight
J2 - JCI Insight
PY - 2026
DA - 2026/07/14
VL - 11
IS - 16
SP - e200106
SN - 2379-3708
PB - American Society for Clinical Investigation
DO - 10.1172/jci.insight.200106
UR - https://doi.org/10.1172/jci.insight.200106
LA - en
ER -

CSL-JSON

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