Peripheral Neuropathy and Decreased Locomotion of a RAB40B Mutation in Human and Model Animals

다국어 초록 (Multilingual Abstract)

Rab40 proteins are an atypical subgroup of Rab GTPases containing a unique suppressor of the cytokine signaling (SOCS) domain that is recruitedto assemble the CRL5 E3 ligase complex for proteolytic regulation in various biological processes. A nonsense mutation deleting the C-terminalSOCS box in the RAB40B gene was identified in a family with axonal peripheral neuropathy (Charcot-Marie-Tooth disease type 2), and pathogenicityof the mutation was assessed in model organisms of zebrafish and Drosophila . Compared to control fish, zebrafish larvae transformed by thehuman mutant hRAB40B-Y83X showed a defective swimming pattern of stalling with restricted localization and slower motility. We were consistentlyable to observe reduced labeling of synaptic markers along neuromuscular junctions of the transformed larvae. In addition to the neurodevelopmentalphenotypes, compared to normal hRAB40B expression, we further examined ectopic expression of hRAB40B-Y83X in Drosophila toshow a progressive decline of locomotion ability. Decreased ability of locomotion by ubiquitous expression of the human mutation was reproducednot with GAL4 drivers for neuron-specific expression but only when a pan-glial GAL4 driver was applied. Using the ectopic expression model ofDrosophila , we identified a genetic interaction in which Cul5 down regulation exacerbated the defective motor performance, showing a consistentloss of SOCS box of the pathogenic RAB40B. Taken together, we could assess the possible gain-of-function of the human RAB40B mutation bycomparing behavioral phenotypes in animal models; our results suggest that the mutant phenotypes may be associated with CRL5-mediated proteolyticregulation.