title: Defective axonal transport of Rab7 GTPase results in dysregulated trophic signaling.
abstract: Retrograde trophic signaling of nerve growth factor (NGF) supports neuronal survival and differentiation. Dysregulated trophic signaling could lead to various neurological disorders. Charcot-Marie-Tooth type 2B (CMT2B) is one of the most common inherited peripheral neuropathies characterized by severe terminal axonal loss. Genetic analysis of human CMT2B patients has revealed four missense point mutations in Rab7, a small GTPase that regulates late endosomal/lysosomal pathways, but the exact pathological mechanism remains poorly understood. Here, we show that these Rab7 mutants dysregulated axonal transport and diminished the retrograde signaling of NGF and its TrkA receptor. We found that all CMT2B Rab7 mutants were transported significantly faster than Rab7(wt) in the anterograde direction, accompanied with an increased percentile of anterograde Rab7-vesicles within axons of rat E15.5 dorsal root ganglion (DRG) neurons. In PC12M cells, the CMT2B Rab7 mutants drastically reduced the level of surface TrkA and NGF binding, presumably by premature degradation of TrkA. On the other hand, siRNA knock-down of endogenous Rab7 led to the appearance of large TrkA puncta in enlarged Rab5-early endosomes within the cytoplasm, suggesting delayed TrkA degradation. We also show that CMT2B Rab7 mutants markedly impaired NGF-induced Erk1/2 activation and differentiation in PC12M cells. Further analysis revealed that CMT2B Rab7 mutants caused axonal degeneration in rat E15.5 DRG neurons. We propose that Rab7 mutants induce premature degradation of retrograde NGF-TrkA trophic signaling, which may potentially contribute to the CMT2B disease.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Rotem
authors.initials: R
authors.lastname: Fishel Ben Kenan
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Osakada
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Sinit
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.forename: Jia-Yun
authors.initials: JY
authors.lastname: Chen
authors.forename: Bianxiao
authors.initials: B
authors.lastname: Cui
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004285:Dogs; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000083083:Laminopathies; D016716:PC12 Cells; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D017978:Receptors, Growth Factor; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716466:rab7 GTP-binding proteins, rat; D020691:rab GTP-Binding Proteins