title: Charcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function.
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. DOI: http://dx.doi.org/10.7554/eLife.01064.001.
authors: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States.
authors: Smita
authors: S
authors: Cherry
authors: Eugene Jennifer
authors: EJ
authors: Jin
authors: Mehmet Neset
authors: MN
authors: Ozel
authors: Zhiyuan
authors: Z
authors: Lu
authors: Egemen
authors: E
authors: Agi
authors: Dong
authors: D
authors: Wang
authors: Wei-Hung
authors: WH
authors: Jung
authors: Daniel
authors: D
authors: Epstein
authors: Ian A
authors: IA
authors: Meinertzhagen
authors: Chih-Chiang
authors: CC
authors: Chan
authors: P Robin
authors: PR
authors: Hiesinger
mesh_terms: D000818:Animals; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D004195:Disease Models, Animal; D004330:Drosophila; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D000083083:Laminopathies; D008969:Molecular Sequence Data; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*; D011984:Sensory Receptor Cells / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000090802:rab7 GTP-Binding Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020691:rab GTP-Binding Proteins
keywords: endosome; genetics; neuropathy; synapse