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J. Biol. Chem., Vol. 280, Issue 51, 42336-42344, December 23, 2005

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Tetanus Toxin Is Transported in a Novel Neuronal Compartment Characterized by a Specialized pH Regulation^*

From the Molecular NeuroPathobiology Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Tetanus toxin binds specifically to motor neurons at the neuromuscular junction. There, it is internalized into vesicular carriers undergoing fast retrograde transport to the spinal cord. Despite the importance of this axonal transport pathway in health and disease, its molecular and biophysical characterization is presently lacking. We sought to fill this gap by determining the pH regulation of this compartment in living motor neurons using a chimera of the tetanus toxin binding fragment (TeNT H_C) and a pH-sensitive variant of the green fluorescent protein (ratiometric pHluorin). We have demonstrated that moving retrograde carriers display a narrow range of neutral pH values, which is kept constant during transport. Stationary TeNT H_C-positive organelles instead exhibit a wide spectrum of pH values, ranging from acidic to neutral. This distinct pH regulation is due to a differential targeting of the vacuolar (H⁺) ATPase, which is not present on moving TeNT H_C compartments. Accordingly, inhibition of the vacuolar (H⁺) ATPase under conditions that completely abolish the intracellular accumulation of acidotrophic dyes does not affect axonal retrograde transport of TeNT H_C.However, a functional vacuolar (H⁺) ATPase is required for early steps of TeNT H_C trafficking following endocytosis, and it is localized to axonal vesicles containing TeNT H_C. Altogether, these findings indicate that the vacuolar (H⁺) ATPase plays a specific role in early sorting events directing TeNT H_C to axonal carriers but not in their subsequent progression along the retrograde transport route, which escapes acidification and targeting to degradative organelles.

Received for publication, June 21, 2005 , and in revised form, October 11, 2005.

^* This work was supported by Cancer Research UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4 and Videos 1 (a-c) and 2 (a-e).

¹ To whom correspondence should be addressed: Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. Tel.: 44-20-7269-3300; Fax 44-20-7269-3417; E-mail: Giampietro.Schiavo{at}cancer.org.uk.

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