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Stathmin 1/2-triggered microtubule loss mediates Golgi fragmentation in mutant SOD1 motor neurons

Abstract : Background: Pathological Golgi fragmentation represents a constant pre-clinical feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) but its molecular mechanisms remain hitherto unclear. Results: Here, we show that the severe Golgi fragmentation in transgenic mutant SOD1 G85R and SOD1 G93A mouse motor neurons is associated with defective polymerization of Golgi-derived microtubules, loss of the COPI coat subunit β-COP, cytoplasmic dispersion of the Golgi tether GM130, strong accumulation of the ER-Golgi v-SNAREs GS15 and GS28 as well as tubular/vesicular Golgi fragmentation. Data mining, transcriptomic and protein analyses demonstrate that both SOD1 mutants cause early presymptomatic and rapidly progressive up-regulation of the microtubule-destabilizing proteins Stathmins 1 and 2. Remarkably, mutant SOD1-triggered Golgi fragmentation and Golgi SNARE accumulation are recapitulated by Stathmin 1/2 overexpression but completely rescued by Stathmin 1/2 knockdown or the microtubule-stabilizing drug Taxol. Conclusions: We conclude that Stathmin-triggered microtubule destabilization mediates Golgi fragmentation in mutant SOD1-linked ALS and potentially also in related motor neuron diseases.
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Sarah Bellouze, Gilbert Baillat, Dorothée Buttigieg, Pierre de la Grange, Catherine Rabouille, et al.. Stathmin 1/2-triggered microtubule loss mediates Golgi fragmentation in mutant SOD1 motor neurons. Molecular Neurodegeneration, BioMed Central, 2016, 11, pp.43. ⟨10.1186/s13024-016-0111-6⟩. ⟨hal-01463801⟩

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