Charcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function.

Cherry, S., Jin, E.J., Ozel, M.N., Lu, Z., Agi, E., Wang, D., Meinertzhagen, I.A., Chan, C.-C., and Hiesinger, P.R.— 2013

The 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. DOI: http://dx.doi.org/10.7554/eLife.01064.001.

TitleCharcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function.
AuthorCherry, S., Jin, E.J., Ozel, M.N., Lu, Z., Agi, E., Wang, D., Meinertzhagen, I.A., Chan, C.-C., and Hiesinger, P.R.
PublishereLife Sciences Publications, Ltd.
Subjectendosome; genetics; neuropathy; synapse
Date20131210
Identifierdoi: 10.7554/eLife.01064
Source(s)
Relation
Appeared InElife 2: e01064
Languageeng
TypeText
Rights© 2013 Cherry et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.