Guo, Yan;
Xiang, Pan;
Sun, Xiaojiao;
Liu, Wei;
Zhou, Jiafeng;
Yin, Bin;
Hou, Lin;
... Peng, Xiaozhong; + view all
(2024)
Docking protein 6 (DOK6) selectively docks the neurotrophic signaling transduction to restrain peripheral neuropathy.
Signal Transduction and Targeted Therapy
, 9
(1)
, Article 32. 10.1038/s41392-024-01742-2.
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Abstract
The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits, and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways. Here, we identified that DOK6, a member of the Dok (downstream of tyrosine kinases) family, is required for the maintenance of peripheral axons, and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice, manifested as impaired sensory, abnormal posture, paw deformities, blocked nerve conduction, and dysmyelination. Furthermore, Dok6 is highly expressed in peripheral neurons but not in Schwann cells, and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding, axon destruction, and hindered retrograde axonal transport. Specifically, DOK6 acts as an adaptor protein for selectivity-mediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and TrkB. DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation, including MAP1B, Tau and Dynein for axonal transport, and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis. This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.
| Type: | Article |
|---|---|
| Title: | Docking protein 6 (DOK6) selectively docks the neurotrophic signaling transduction to restrain peripheral neuropathy |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41392-024-01742-2 |
| Publisher version: | https://doi.org/10.1038/s41392-024-01742-2 |
| Language: | English |
| Additional information: | © 2024 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Mice, Animals, Peripheral Nervous System Diseases, Signal Transduction, Axons, Neurons, Adaptor Proteins, Signal Transducing |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10187387 |
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