Docking protein 6 (DOK6) selectively docks the neurotrophic signaling transduction to restrain peripheral neuropathy  

作　　者：Yan Guo Pan Xiang Xiaojiao Sun Wei Liu Jiafeng Zhou Bin Yin Lin Hou Boqin Qiang Huiliang Li Pengcheng Shu Xiaozhong Peng 

机构地区：[1]Department of Molecular Biology and Biochemistry,Institute of Basic Medical Sciences,Medical Primate Research Center,Neuroscience Center,Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College,Beijing,China [2]State Key Laboratory of Common Mechanism Research for Major Diseases,Beijing 100005,China [3]Wolfson Institute for Biomedical Research,University College London,Gower Street,London WC1E 6BT,UK [4]Chinese Institute for Brain Research,Beijing 102206,China [5]State Key Laboratory of Respiratory Health and Multimorbidity,Beijing 100005,China [6]Institute of Laboratory Animal Science,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100021,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第3期1147-1164,共18页信号转导与靶向治疗（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(32370883);National Science and Technology Innovation 2030 Grants(2021ZD0200902);the CAMS Innovation Fund for Medical Sciences(CIFMS;2021-I2M-1-019 and 2021-I2M-1-024).

摘　　要：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 selectivitymediated 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.

关 键 词：IMPAIRED restrain PERIPHERAL 

分 类 号：R741[医药卫生—神经病学与精神病学]