title: Golgi fragmentation in pmn mice is due to a defective ARF1/TBCE cross-talk that coordinates COPI vesicle formation and tubulin polymerization.
abstract: Golgi fragmentation is an early hallmark of many neurodegenerative diseases but its pathophysiological relevance and molecular mechanisms are unclear. We here demonstrate severe and progressive Golgi fragmentation in motor neurons of progressive motor neuronopathy (pmn) mice due to loss of the Golgi-localized tubulin-binding cofactor E (TBCE). Loss of TBCE in mutant pmn and TBCE-depleted motor neuron cultures causes defects in Golgi-derived microtubules, as expected, but surprisingly also reduced levels of COPI subunits, decreased recruitment of tethering factors p115/GM130 and impaired Golgi SNARE-mediated vesicle fusion. Conversely, ARF1, which stimulates COPI vesicle formation, enhances the recruitment of TBCE to the Golgi, increases polymerization of Golgi-derived microtubules and rescues TBCE-linked Golgi fragmentation. These data indicate an ARF1/TBCE-mediated cross-talk that coordinates COPI formation and tubulin polymerization at the Golgi. We conclude that interruption of this cross-talk causes Golgi fragmentation in pmn mice and hypothesize that similar mechanisms operate in human amyotrophic lateral sclerosis and spinal muscular atrophy.
authors.affiliation: Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université UMR7289, Marseille, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bellouze
authors.affiliation: Klinik für Anästhesiologie, Universitätsmedizin Mainz, Mainz, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schäfer
authors.affiliation: Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université UMR7289, Marseille, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Buttigieg
authors.affiliation: Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université UMR7289, Marseille, France.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Baillat
authors.affiliation: Hubrecht Institute-KNAW and Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rabouille
authors.affiliation: Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université UMR7289, Marseille, France, georg.haase@univ-amu.fr.
authors.forename: Georg
authors.initials: G
authors.lastname: Haase
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D022181:COP-Coated Vesicles / Q000235:genetics / Q000378:metabolism*; D020755:Coat Protein Complex I / Q000378:metabolism; D004195:Disease Models, Animal; D006056:Golgi Apparatus / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000737:chemistry / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D058105:Polymerization; D015398:Signal Transduction; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020755:Coat Protein Complex I; D018832:Molecular Chaperones; C469269:Tbce protein, mouse; D014404:Tubulin; D020823:ADP-Ribosylation Factor 1