HDAC6 inhibition alleviates mitochondrial trafficking in novel models of Charcot-Marie-Tooth Disease Type 2A

Lydia H. Jestice; Larissa Butler; Rebecca A. Lea; Kathryn I. Adamson; Jonas Van Lent; Stuart L. Johnson; Hollie Weedon; Eldriena D’Silva; Gabriele Gelezauskaite; Bob Asselbergh; Eloise Brown; Owen Laing; Christopher J. Price; Dylan Stavish; Anestis Tsakiridis; Mark O. Collins; Vincent Timmerman; Kurt J. De Vos; Alison E. Twelvetrees; Andrew J. Grierson; Ivana Barbaric

doi:10.1172/jci.insight.200106

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Jestice, L. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

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¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Lea, R. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Adamson, K. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Van Lent, J. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Johnson, S. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Weedon, H. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by D’Silva, E. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Gelezauskaite, G. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Asselbergh, B. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Brown, E. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Laing, O. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Price, C. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Stavish, D. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Tsakiridis, A. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Collins, M. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Timmerman, V. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by De Vos, K. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Twelvetrees, A. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Grierson, A. in: PubMed | Google Scholar

¹School of Biosciences, The University of Sheffield, Sheffield, United Kingdom

²Neuroscience Institute, The University of Sheffield, Sheffield, United Kingdom

³Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

⁴VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Find articles by Barbaric, I. in: PubMed | Google Scholar

JCI Insight. https://doi.org/10.1172/jci.insight.200106.
Copyright © 2026, Jestice et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published July 14, 2026 - Version history

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 MFN2^R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2^R94Q/+ 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.

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HDAC6 inhibition alleviates mitochondrial trafficking in novel models of Charcot-Marie-Tooth Disease Type 2A

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