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
Affiliations
Smita Cherry
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
Eugene Jennifer Jin
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
Mehmet Neset Özel
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
Zhiyuan Lu
Department of Psychology and Neuroscience, Dalhousie University, Halifax, Canada
Egemen Agi
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
Dong Wang
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
Wei-Hung Jung
Department of Physiology, National Taiwan University, Taipei, Taiwan
Daniel Epstein
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
Ian A Meinertzhagen
Department of Psychology and Neuroscience, Dalhousie University, Halifax, Canada
Chih-Chiang Chan
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Physiology, National Taiwan University, Taipei, Taiwan
P Robin Hiesinger
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States; Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, United States
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.
