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Mol Neurodegener. 2016 Jun 9;11(1):43. doi: 10.1186/s13024-016-0111-6.

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

Author information

1
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.
2
GenoSplice technology, iPEPS - ICM, Hôpital Pitié Salpêtrière, 47/83, bd de l'Hôpital, 75013 Paris, France.
3
Department of Cell Biology, Hubrecht Institute of the KNAW & UMC Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.
4
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.

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.

PMID:
27277231
PMCID:
PMC4899909
DOI:
10.1186/s13024-016-0111-6
[Indexed for MEDLINE]
Free PMC Article

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