Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice
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 characterizing Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different pro...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.157191 |
| _version_ | 1797634319020195840 |
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| author | James N. Sleigh David Villarroel-Campos Sunaina Surana Tahmina Wickenden Yao Tong Rebecca L. Simkin Jose Norberto S. Vargas Elena R. Rhymes Andrew P. Tosolini Steven J. West Qian Zhang Xiang-Lei Yang Giampietro Schiavo |
| author_facet | James N. Sleigh David Villarroel-Campos Sunaina Surana Tahmina Wickenden Yao Tong Rebecca L. Simkin Jose Norberto S. Vargas Elena R. Rhymes Andrew P. Tosolini Steven J. West Qian Zhang Xiang-Lei Yang Giampietro Schiavo |
| author_sort | James N. Sleigh |
| collection | DOAJ |
| description | 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 characterizing Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor tropomyosin receptor kinase receptor B (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 displayed early and persistent disturbances in axonal transport of neurotrophin-containing signaling endosomes in vivo. We discovered that brain-derived neurotrophic factor (BDNF)/TrkB impairments correlated with transport disruption and overall CMT2D neuropathology and that inhibition of this pathway at the nerve-muscle interface perturbed endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restored 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. |
| first_indexed | 2024-03-11T12:05:58Z |
| format | Article |
| id | doaj.art-b67b689534054283ad3f0ed434509f29 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:58Z |
| publishDate | 2023-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b67b689534054283ad3f0ed434509f292023-11-07T16:25:35ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-05-0189Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D miceJames N. SleighDavid Villarroel-CamposSunaina SuranaTahmina WickendenYao TongRebecca L. SimkinJose Norberto S. VargasElena R. RhymesAndrew P. TosoliniSteven J. WestQian ZhangXiang-Lei YangGiampietro SchiavoGain-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 characterizing Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor tropomyosin receptor kinase receptor B (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 displayed early and persistent disturbances in axonal transport of neurotrophin-containing signaling endosomes in vivo. We discovered that brain-derived neurotrophic factor (BDNF)/TrkB impairments correlated with transport disruption and overall CMT2D neuropathology and that inhibition of this pathway at the nerve-muscle interface perturbed endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restored 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.https://doi.org/10.1172/jci.insight.157191Neuroscience |
| spellingShingle | James N. Sleigh David Villarroel-Campos Sunaina Surana Tahmina Wickenden Yao Tong Rebecca L. Simkin Jose Norberto S. Vargas Elena R. Rhymes Andrew P. Tosolini Steven J. West Qian Zhang Xiang-Lei Yang Giampietro Schiavo Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice JCI Insight Neuroscience |
| title | Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice |
| title_full | Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice |
| title_fullStr | Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice |
| title_full_unstemmed | Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice |
| title_short | Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice |
| title_sort | boosting peripheral bdnf rescues impaired in vivo axonal transport in cmt2d mice |
| topic | Neuroscience |
| url | https://doi.org/10.1172/jci.insight.157191 |
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