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Charcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function.
Cherry, Smita; Jin, Eugene Jennifer; Ozel, Mehmet Neset; Lu, Zhiyuan; Agi, Egemen; Wang, Dong; Jung, Wei-Hung; Epstein, Daniel; Meinertzhagen, Ian A; Chan, Chih-Chiang; Hiesinger, P Robin.
Affiliation
  • Cherry S; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States.
Elife ; 2: e01064, 2013 Dec 10.
Article in En | MEDLINE | ID: mdl-24327558
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Charcot-Marie-Tooth Disease / Neurodegenerative Diseases / Rab GTP-Binding Proteins / Mutation Type of study: Prognostic_studies Limits: Animals Language: En Journal: Elife Year: 2013 Document type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Charcot-Marie-Tooth Disease / Neurodegenerative Diseases / Rab GTP-Binding Proteins / Mutation Type of study: Prognostic_studies Limits: Animals Language: En Journal: Elife Year: 2013 Document type: Article Affiliation country: United States