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ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/jci.insight.157191

Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice

James N. Sleigh,1 David Villarroel-Campos,1 Sunaina Surana,1 Tahmina Wickenden,1 Yao Tong,2 Rebecca L. Simkin,1 Jose Norberto S. Vargas,1 Elena R. Rhymes,1 Andrew P. Tosolini,1 Steven J. West,3 Qian Zhang,2 Xiang-Lei Yang,2 and Giampietro Schiavo1

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

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1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

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1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

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

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

Find articles by Wickenden, T. in: JCI | PubMed | Google Scholar

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

Find articles by Tong, Y. in: JCI | PubMed | Google Scholar

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

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

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

Find articles by Vargas, J. in: JCI | PubMed | Google Scholar |

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

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

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

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

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

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

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

Find articles by Zhang, Q. in: JCI | PubMed | Google Scholar

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

Find articles by Yang, X. in: JCI | PubMed | Google Scholar |

1Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, United Kingdom

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Sainsbury Wellcome Centre, University College London, London, United Kingdom

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

Published March 16, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.157191.
Copyright © 2023, Sleigh 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 March 16, 2023 - Version history
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Abstract

Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterising Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor TrkB, underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice display early and persistent disturbances in axonal transport of neurotrophin-containing signalling endosomes in vivo. We discovered that BDNF-TrkB impairments correlate with transport disruption and overall CMT2D neuropathology, and that inhibition of this pathway at the nerve-muscle interface perturbs endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restores physiological axonal transport in neuropathic mice. Together, these findings suggest that selectively targeting muscles with BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.

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