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Articles, Cellular/Molecular

Defective Axonal Transport of Rab7 GTPase Results in Dysregulated Trophic Signaling

Kai Zhang, Rotem Fishel Ben Kenan, Yasuko Osakada, Wei Xu, Rachel S. Sinit, Liang Chen, Xiaobei Zhao, Jia-Yun Chen, Bianxiao Cui and Chengbiao Wu
Journal of Neuroscience 24 April 2013, 33 (17) 7451-7462; https://doi.org/10.1523/JNEUROSCI.4322-12.2013
Kai Zhang
1Department of Chemistry, Stanford University, Stanford, California 94305,
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Rotem Fishel Ben Kenan
2Department of Neurosciences, University of California, San Diego, La Jolla, California 92093,
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Yasuko Osakada
1Department of Chemistry, Stanford University, Stanford, California 94305,
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Wei Xu
2Department of Neurosciences, University of California, San Diego, La Jolla, California 92093,
3Department of Neurology & Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China,
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Rachel S. Sinit
2Department of Neurosciences, University of California, San Diego, La Jolla, California 92093,
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Liang Chen
4Lawrence Berkeley National Laboratory, Berkeley, California 94720, and
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Xiaobei Zhao
2Department of Neurosciences, University of California, San Diego, La Jolla, California 92093,
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Jia-Yun Chen
5Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305
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Bianxiao Cui
1Department of Chemistry, Stanford University, Stanford, California 94305,
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Chengbiao Wu
2Department of Neurosciences, University of California, San Diego, La Jolla, California 92093,
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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 Rab7wt 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.

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The Journal of Neuroscience: 33 (17)
Journal of Neuroscience
Vol. 33, Issue 17
24 Apr 2013
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Defective Axonal Transport of Rab7 GTPase Results in Dysregulated Trophic Signaling
Kai Zhang, Rotem Fishel Ben Kenan, Yasuko Osakada, Wei Xu, Rachel S. Sinit, Liang Chen, Xiaobei Zhao, Jia-Yun Chen, Bianxiao Cui, Chengbiao Wu
Journal of Neuroscience 24 April 2013, 33 (17) 7451-7462; DOI: 10.1523/JNEUROSCI.4322-12.2013

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Defective Axonal Transport of Rab7 GTPase Results in Dysregulated Trophic Signaling
Kai Zhang, Rotem Fishel Ben Kenan, Yasuko Osakada, Wei Xu, Rachel S. Sinit, Liang Chen, Xiaobei Zhao, Jia-Yun Chen, Bianxiao Cui, Chengbiao Wu
Journal of Neuroscience 24 April 2013, 33 (17) 7451-7462; DOI: 10.1523/JNEUROSCI.4322-12.2013
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