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 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.
Schaefer
Michael K E
MK
Inserm, Unité 29, Equipe Avenir, Marseille, France.
Schmalbruch
Henning
H
Buhler
Emmanuelle
E
Lopez
Catherine
C
Martin
Natalia
N
Guénet
Jean-Louis
JL
Haase
Georg
G
D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008870:Microtubules / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*; D016472:Motor Neuron Disease / Q000473:pathology*; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure*; D009410:Nerve Degeneration / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism*
D018832:Molecular Chaperones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C469269:Tbce protein, mouse; D014404:Tubulin; D049452:Green Fluorescent Proteins
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