title: Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking.
abstract: The mechanisms regulating synapse numbers during development and ageing are essential for normal brain function and closely linked to brain disorders including dementias. Using Drosophila, we demonstrate roles of the microtubule-associated protein Tau in regulating synapse numbers, thus unravelling an important cellular requirement of normal Tau. In this context, we find that Tau displays a strong functional overlap with microtubule-binding spectraplakins, establishing new links between two different neurodegenerative factors. Tau and the spectraplakin Short Stop act upstream of a three-step regulatory cascade ensuring adequate delivery of synaptic proteins. This cascade involves microtubule stability as the initial trigger, JNK signalling as the central mediator, and kinesin-3 mediated axonal transport as the key effector. This cascade acts during development (synapse formation) and ageing (synapse maintenance) alike. Therefore, our findings suggest novel explanations for intellectual disability in Tau deficient individuals, as well as early synapse loss in dementias including Alzheimer's disease.
authors: Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom.
authors: Andre
authors: 0000-0002-7682-5637
authors: A
authors: Voelzmann
authors: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors: Pilar
authors: 0000-0002-7513-6557
authors: P
authors: Okenve-Ramos
authors: Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom.
authors: Yue
authors: 0000-0002-2593-3654
authors: Y
authors: Qu
authors: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors: Monika
authors: M
authors: Chojnowska-Monga
authors: Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
authors: Manuela
authors: M
authors: Del Caño-Espinel
authors: Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom.
authors: Andreas
authors: 0000-0001-8482-3298
authors: A
authors: Prokop
authors: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors: Natalia
authors: 0000-0002-6667-2817
authors: N
authors: Sanchez-Soriano
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001370:Axonal Transport; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D002465:Cell Movement; D003704:Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D021381:Protein Transport; D015398:Signal Transduction; D013569:Synapses / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D008840:Microfilament Proteins; C450828:shot protein, Drosophila; D016875:tau Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D016547:Kinesins
keywords: D. melanogaster; axons; developmental biology; microtubules; neurodegeneration; neuroscience; stem cells; synapses; tau; transport