RESUMEN
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.
Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Exocitosis , Histona Desacetilasas/metabolismo , Neurotransmisores/metabolismo , Animales , Proteínas de Unión al ADN/metabolismo , Drosophila/enzimología , Proteínas de Drosophila/genética , Histona Acetiltransferasas/metabolismo , Histona Desacetilasa 6 , Histona Desacetilasas/genética , Proteínas del Tejido Nervioso/metabolismo , Sinapsis/metabolismo , Sinapsis/ultraestructuraRESUMEN
Elongator protein 3 (ELP3) acetylates histones in the nucleus but also plays a role in the cytoplasm. Here, we report that in Drosophila neurons, ELP3 is necessary and sufficient to acetylate the ELKS family member Bruchpilot, an integral component of the presynaptic density where neurotransmitters are released. We find that in elp3 mutants, presynaptic densities assemble normally, but they show morphological defects such that their cytoplasmic extensions cover a larger area, resulting in increased vesicle tethering as well as a more proficient neurotransmitter release. We propose a model where ELP3-dependent acetylation of Bruchpilot at synapses regulates the structure of individual presynaptic densities and neurotransmitter release efficiency.
