TY - JOUR
T1 - Charcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function
AU - Cherry, Smita
AU - Jin, Eugene Jennifer
AU - Özel, Mehmet Neset
AU - Lu, Zhiyuan
AU - Agi, Egemen
AU - Wang, Dong
AU - Jung, Wei Hung
AU - Epstein, Daniel
AU - Meinertzhagen, Ian A.
AU - Chan, Chih Chiang
AU - Robin Hiesinger, P.
PY - 2013/12/10
Y1 - 2013/12/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84890407183&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890407183&partnerID=8YFLogxK
U2 - 10.7554/eLife.01064.001
DO - 10.7554/eLife.01064.001
M3 - Article
C2 - 23853192
AN - SCOPUS:84890407183
SN - 2050-084X
VL - 2013
JO - eLife
JF - eLife
IS - 2
M1 - e01064
ER -