Cherry S.Jin E.J.Özel M.N.Lu Z.Agi E.Wang D.Jung W.-H.Epstein D.Meinertzhagen I.A.CHIH-CHIANG CHANRobin Hiesinger P.2020-07-012020-07-0120132050-084Xhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84890407183&doi=10.7554%2feLife.01064.001&partnerID=40&md5=c29e5c2723ce51907299c4c3ea17ec54https://scholars.lib.ntu.edu.tw/handle/123456789/507596The small GTPase Rab7 is a key regulator of endosomal maturation in eukaryotic cells. Mutations in rab7 are thought to cause the dominant neuropathy Charcot-Marie-Tooth 2B (CMT2B) by a gain-of-function mechanism. Here we show that loss of rab7, but not overexpression of rab7 CMT2B mutants, causes adult-onset neurodegeneration in a Drosophila model. All CMT2B mutant proteins retain 10-50% function based on quantitative imaging, electrophysiology, and rescue experiments in sensory and motor neurons in vivo. Consequently, expression of CMT2B mutants at levels between 0.5 and 10-fold their endogenous levels fully rescues the neuropathy-like phenotypes of the rab7 mutant. Live imaging reveals that CMT2B proteins are inefficiently recruited to endosomes, but do not impair endosomal maturation. These findings are not consistent with a gain-of-function mechanism. Instead, they indicate a dosage-dependent sensitivity of neurons to rab7-dependent degradation. Our results suggest a therapeutic approach opposite to the currently proposed reduction of mutant protein function. ? Dellas et al.[SDGs]SDG3Rab7 protein; animal experiment; animal tissue; article; Charcot Marie Tooth 2B gene; confocal microscopy; controlled study; Drosophila; electrophysiology; electroretinography; gene; gene expression; gene mutation; image processing; immunohistochemistry; nerve degeneration; neuromuscular synapse; neuropathy; nonhuman; photoreceptor; polymerase chain reaction; protein degradation; sensory nerve cell; transmission electron microscopy; Western blotting; Charcot-Marie-Tooth Disease; Humans; Male; Middle Aged; Neurofibromatoses; Neurofibromatosis 1; Peripheral Nervous System Neoplasms; Spinal Nerve Rootsjournal article10.7554/eLife.01064.001238531922-s2.0-84890407183