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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.

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