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

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 demon-strate that TBCE is a peripheralmembrane-associatedprotein that accumulates at theGolgi apparatus. Inpmnmice, 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 theGolgi apparatus. In culturedmotor neurons, the pmn mutation, interference RNA-mediated TBCE depletion, and brefeldin A-mediated Golgi disruption all compromise axonal tubulin rout-ing.Weconclude thatmotor axons criticallydependonaxonal tubulin routing fromtheGolgi apparatus, aprocess that involvesTBCEand possibly other tubulin chaperones. Key words:motor neuron disease; ALS; axon degeneration; tubulin chaperone; microtubules; Golgi apparatu