title: HDAC6 is a Bruchpilot deacetylase that facilitates neurotransmitter release.
abstract: Presynaptic densities are specialized structures involved in synaptic vesicle tethering and neurotransmission; however, the mechanisms regulating their function remain understudied. In Drosophila, Bruchpilot is a major constituent of the presynaptic density that tethers vesicles. Here, we show that HDAC6 is necessary and sufficient for deacetylation of Bruchpilot. HDAC6 expression is also controlled by TDP-43, an RNA-binding protein deregulated in amyotrophic lateral sclerosis (ALS). Animals expressing TDP-43 harboring pathogenic mutations show increased HDAC6 expression, decreased Bruchpilot acetylation, larger vesicle-tethering sites, and increased neurotransmission, defects similar to those seen upon expression of HDAC6 and opposite to hdac6 null mutants. Consequently, reduced levels of HDAC6 or increased levels of ELP3, a Bruchpilot acetyltransferase, rescue the presynaptic density defects in TDP-43-expressing flies as well as the decreased adult locomotion. Our work identifies HDAC6 as a Bruchpilot deacetylase and indicates that regulating acetylation of a presynaptic release-site protein is critical for maintaining normal neurotransmission.
authors: VIB Center for the Biology of Disease, Herestraat 49 bus 602, 3000 Leuven, Belgium; KU Leuven, Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), Herestraat 49 bus 602, 3000 Leuven, Belgium.
authors: Katarzyna
authors: K
authors: Miskiewicz
authors: VIB Center for the Biology of Disease, Herestraat 49 bus 602, 3000 Leuven, Belgium; KU Leuven, Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), Herestraat 49 bus 602, 3000 Leuven, Belgium.
authors: Liya E
authors: LE
authors: Jose
authors: VIB Center for the Biology of Disease, Herestraat 49 bus 602, 3000 Leuven, Belgium; KU Leuven, Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), Herestraat 49 bus 602, 3000 Leuven, Belgium.
authors: Wondwossen M
authors: WM
authors: Yeshaw
authors: VIB Center for the Biology of Disease, Herestraat 49 bus 602, 3000 Leuven, Belgium; KU Leuven, Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), Herestraat 49 bus 602, 3000 Leuven, Belgium.
authors: Jorge S
authors: JS
authors: Valadas
authors: VIB Center for the Biology of Disease, Herestraat 49 bus 602, 3000 Leuven, Belgium; KU Leuven, Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), Herestraat 49 bus 602, 3000 Leuven, Belgium.
authors: Jef
authors: J
authors: Swerts
authors: VIB Center for the Biology of Disease, Herestraat 49 bus 602, 3000 Leuven, Belgium; KU Leuven, Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), Herestraat 49 bus 602, 3000 Leuven, Belgium; VIB Bio Imaging Core, Herestraat 49 bus 602, 3000 Leuven, Belgium.
authors: Sebastian
authors: S
authors: Munck
authors: International Center for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors: Fabian
authors: F
authors: Feiguin
authors: INSERM U744, Institut Pasteur de Lille, Université de Lille Nord de France, rue du Professeur Calmette 1, 59019 Lille, France; Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium.
authors: Bart
authors: B
authors: Dermaut
authors: VIB Center for the Biology of Disease, Herestraat 49 bus 602, 3000 Leuven, Belgium; KU Leuven, Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), Herestraat 49 bus 602, 3000 Leuven, Belgium. Electronic address: patrik.verstreken@cme.vib-kuleuven.be.
authors: Patrik
authors: P
authors: Verstreken
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila / Q000201:enzymology / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005089:Exocytosis; D051548:Histone Acetyltransferases / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure
chemical_list: C510146:BRP protein, Drosophila; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C000589036:TBPH protein, Drosophila; C538730:ELP3 protein, Drosophila; D051548:Histone Acetyltransferases; C425683:HDAC6 protein, Drosophila; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases