Wonseok Son, Hui Su Jeong, Da Eun Nam, Ah Jin Lee, Soo Hyun Nam, Ji Eun Lee, Byung-Ok Choi, Ki Wha Chung
{"title":"Peripheral Neuropathy and Decreased Locomotion of a <i>RAB40B</i> Mutation in Human and Model Animals.","authors":"Wonseok Son, Hui Su Jeong, Da Eun Nam, Ah Jin Lee, Soo Hyun Nam, Ji Eun Lee, Byung-Ok Choi, Ki Wha Chung","doi":"10.5607/en23027","DOIUrl":null,"url":null,"abstract":"<p><p>Rab40 proteins are an atypical subgroup of Rab GTPases containing a unique suppressor of the cytokine signaling (SOCS) domain that is recruited to assemble the CRL5 E3 ligase complex for proteolytic regulation in various biological processes. A nonsense mutation deleting the C-terminal SOCS box in the <i>RAB40B</i> gene was identified in a family with axonal peripheral neuropathy (Charcot-Marie-Tooth disease type 2), and pathogenicity of the mutation was assessed in model organisms of zebrafish and <i>Drosophila</i>. Compared to control fish, zebrafish larvae transformed by the human mutant <i>hRAB40B</i><i>-Y83X</i> showed a defective swimming pattern of stalling with restricted localization and slower motility. We were consistently able to observe reduced labeling of synaptic markers along neuromuscular junctions of the transformed larvae. In addition to the neurodevelopmental phenotypes, compared to normal <i>hRAB40B</i> expression, we further examined ectopic expression of <i>hRAB40B</i><i>-Y83X</i> in <i>Drosophila</i> to show a progressive decline of locomotion ability. Decreased ability of locomotion by ubiquitous expression of the human mutation was reproduced not with GAL4 drivers for neuron-specific expression but only when a pan-glial GAL4 driver was applied. Using the ectopic expression model of <i>Drosophila</i>, we identified a genetic interaction in which <i>Cul5</i> down regulation exacerbated the defective motor performance, showing a consistent loss of SOCS box of the pathogenic RAB40B. Taken together, we could assess the possible gain-of-function of the human <i>RAB40B</i> mutation by comparing behavioral phenotypes in animal models; our results suggest that the mutant phenotypes may be associated with CRL5-mediated proteolytic regulation.</p>","PeriodicalId":12263,"journal":{"name":"Experimental Neurobiology","volume":"32 6","pages":"410-422"},"PeriodicalIF":1.8000,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10789172/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Neurobiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.5607/en23027","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Rab40 proteins are an atypical subgroup of Rab GTPases containing a unique suppressor of the cytokine signaling (SOCS) domain that is recruited to assemble the CRL5 E3 ligase complex for proteolytic regulation in various biological processes. A nonsense mutation deleting the C-terminal SOCS box in the RAB40B gene was identified in a family with axonal peripheral neuropathy (Charcot-Marie-Tooth disease type 2), and pathogenicity of the mutation was assessed in model organisms of zebrafish and Drosophila. Compared to control fish, zebrafish larvae transformed by the human mutant hRAB40B-Y83X showed a defective swimming pattern of stalling with restricted localization and slower motility. We were consistently able to observe reduced labeling of synaptic markers along neuromuscular junctions of the transformed larvae. In addition to the neurodevelopmental phenotypes, compared to normal hRAB40B expression, we further examined ectopic expression of hRAB40B-Y83X in Drosophila to show a progressive decline of locomotion ability. Decreased ability of locomotion by ubiquitous expression of the human mutation was reproduced not with GAL4 drivers for neuron-specific expression but only when a pan-glial GAL4 driver was applied. Using the ectopic expression model of Drosophila, we identified a genetic interaction in which Cul5 down regulation exacerbated the defective motor performance, showing a consistent loss of SOCS box of the pathogenic RAB40B. Taken together, we could assess the possible gain-of-function of the human RAB40B mutation by comparing behavioral phenotypes in animal models; our results suggest that the mutant phenotypes may be associated with CRL5-mediated proteolytic regulation.
期刊介绍:
Experimental Neurobiology is an international forum for interdisciplinary investigations of the nervous system. The journal aims to publish papers that present novel observations in all fields of neuroscience, encompassing cellular & molecular neuroscience, development/differentiation/plasticity, neurobiology of disease, systems/cognitive/behavioral neuroscience, drug development & industrial application, brain-machine interface, methodologies/tools, and clinical neuroscience. It should be of interest to a broad scientific audience working on the biochemical, molecular biological, cell biological, pharmacological, physiological, psychophysical, clinical, anatomical, cognitive, and biotechnological aspects of neuroscience. The journal publishes both original research articles and review articles. Experimental Neurobiology is an open access, peer-reviewed online journal. The journal is published jointly by The Korean Society for Brain and Neural Sciences & The Korean Society for Neurodegenerative Disease.