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

Smita Cherry, Eugene Jennifer Jin, Mehmet Neset Özel, Zhiyuan Lu, Egemen Agi, Dong Wang, Wei Hung Jung, Daniel Epstein, Ian A. Meinertzhagen, Chih Chiang Chan, P. Robin Hiesinger

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere01064
JournaleLife
Volume2013
Issue number2
DOIs
StatePublished - Dec 10 2013

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Cherry, S., Jin, E. J., Özel, M. N., Lu, Z., Agi, E., Wang, D., Jung, W. H., Epstein, D., Meinertzhagen, I. A., Chan, C. C., & Robin Hiesinger, P. (2013). Charcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function. eLife, 2013(2), [e01064]. https://doi.org/10.7554/eLife.01064.001