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



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.



We conclude that Stathmin-triggered microtubule destabilization mediates Golgi fragmentation in mutant SOD1-linked ALS and potentially also in related motor neuron diseases.
Institut de Neurosciences de la Timone, UMR 7289, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université, 27 bd Jean Moulin, 13005 Marseille, France.
Sarah
S
Bellouze
Institut de Neurosciences de la Timone, UMR 7289, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université, 27 bd Jean Moulin, 13005 Marseille, France.
Gilbert
G
Baillat
Institut de Neurosciences de la Timone, UMR 7289, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université, 27 bd Jean Moulin, 13005 Marseille, France.
Dorothée
D
Buttigieg
GenoSplice technology, iPEPS - ICM, Hôpital Pitié Salpêtrière, 47/83, bd de l'Hôpital, 75013 Paris, France.
Pierre
P
de la Grange
Department of Cell Biology, Hubrecht Institute of the KNAW & UMC Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.
Catherine
C
Rabouille
Institut de Neurosciences de la Timone, UMR 7289, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université, 27 bd Jean Moulin, 13005 Marseille, France. georg.haase@univ-amu.fr.
Georg
G
Haase
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D006056:Golgi Apparatus / Q000473:pathology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008870:Microtubules / Q000473:pathology*; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D050777:Stathmin / Q000378:metabolism*; D000072105:Superoxide Dismutase-1 / Q000235:genetics
D050777:Stathmin; D000072105:Superoxide Dismutase-1