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The Journal of Neuroscience, November 23, 2005, 25(47):10930-10940; doi:10.1523/JNEUROSCI.2029-05.2005

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Neurobiology of Disease
The Small GTPase Rab7 Controls the Endosomal Trafficking and Neuritogenic Signaling of the Nerve Growth Factor Receptor TrkA

Smita Saxena,¹ Cecilia Bucci,² Joachim Weis,^1,3 and Alex Kruttgen^1,3

¹Abteilung Neuropathologie, Institut für Pathologie, Universität Bern, CH-3010 Bern, Switzerland, ²Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università di Lecce, 73100 Lecce, Italy, and ³Institut für Neuropathologie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen, D-52074 Aachen, Germany

Nerve growth factor (NGF) and its TrkA receptor exert important bioactivities on neuronal cells such as promoting survival and neurite outgrowth. Activated TrkA receptors are not only localized on the cell surface but also in signaling endosomes, and internalized TrkA receptors are important for the mediation of neurite outgrowth. The regulation of the endosomal trafficking of TrkA is so far unknown. Because the endosome-associated GTPase Rab7 coimmunoprecipitated with TrkA, we examined whether the endosomal trafficking of TrkA might be under the control of Rab7. Inhibiting Rab7 by expression of a green fluorescent protein-tagged, dominant-negative Rab7 variant resulted in endosomal accumulation of TrkA and pronounced enhancement of TrkA signaling in response to limited stimulations with NGF, such as increased activation of Erk1/2 (extracellular signal-regulated kinase 1/2), neurite outgrowth, and expression of GAP-43 (growth-associated protein 43). Our studies show that the endosomal GTPase Rab7 controls the endosomal trafficking and neurite outgrowth signaling of TrkA. Because mutations of Rab7 are found in patients suffering from hereditary polyneuropathies, dysfunction of Rab7 might contribute to neurodegenerative conditions by affecting the trafficking of neurotrophins. Moreover, strategies aimed at controlling Rab7 activity might be useful for the treatment of neurodegenerative diseases.

Key words: polyneuropathy; neurodegeneration; neurotrophin; neurite outgrowth; Charcot-Marie-Tooth; retrograde transport

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Received May 20, 2005; revised October 10, 2005; accepted October 15, 2005.

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