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The Journal of Neuroscience, August 15, 2007, 27(33):8779-8789; doi:10.1523/JNEUROSCI.1599-07.2007

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Neurobiology of Disease
Progressive Motor Neuronopathy: A Critical Role of the Tubulin Chaperone TBCE in Axonal Tubulin Routing from the Golgi Apparatus

Michael K. E. Schaefer,^1,2 Henning Schmalbruch,³ Emmanuelle Buhler,^1,2 Catherine Lopez,^1,2 Natalia Martin,⁴ Jean-Louis Guénet,⁴ and Georg Haase^1,2

¹Inserm, Unité 29, Equipe Avenir, 13273 Marseille, France, ²Aix Marseille Université, Institut de Neurobiologie de la Méditerranée, 13284 Marseille, France, ³Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark, and ⁴Institut Pasteur, 75015 Paris, France

Correspondence should be addressed to Dr. Georg Haase, Institut de Neurobiologie de la Méditerranée, Equipe Avenir, 13288 Marseille cedex 09, France. Email: haase{at}inmed.univ-mrs.fr

Axonal degeneration represents one of the earliest pathological features in motor neuron diseases. We here studied the underlying molecular mechanisms in progressive motor neuronopathy (pmn) mice mutated in the tubulin-specific chaperone TBCE. We demonstrate that TBCE is a peripheral membrane-associated protein that accumulates at the Golgi apparatus. In pmn mice, TBCE is destabilized and disappears from the Golgi apparatus of motor neurons, and microtubules are lost in distal axons. The axonal microtubule loss proceeds retrogradely in parallel with the axonal dying back process. These degenerative changes are inhibited in a dose-dependent manner by transgenic TBCE complementation that restores TBCE expression at the Golgi apparatus. In cultured motor neurons, the pmn mutation, interference RNA-mediated TBCE depletion, and brefeldin A-mediated Golgi disruption all compromise axonal tubulin routing. We conclude that motor axons critically depend on axonal tubulin routing from the Golgi apparatus, a process that involves TBCE and possibly other tubulin chaperones.

Key words: motor neuron disease; ALS; axon degeneration; tubulin chaperone; microtubules; Golgi apparatus

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Received April 10, 2007; revised May 26, 2007; accepted June 21, 2007.

Correspondence should be addressed to Dr. Georg Haase, Institut de Neurobiologie de la Méditerranée, Equipe Avenir, 13288 Marseille cedex 09, France. Email: haase{at}inmed.univ-mrs.fr

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