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oai:riubu.ubu.es:10259/82062023-12-15T01:05:25Zcom_10259_7130com_10259_5086com_10259_2604col_10259_7131

Voelzmann, Andre bdf37f25-7faa-4330-9489-0bed1b4c43bf Okenve-Ramos, Pilar 242fc0fe-73d7-4268-9c33-70d7b8254455 Qu, Yue 455bae5c-26aa-421b-8688-b7eb9cbcba70 Chojnowska-Monga, Monika 442d95f2-28aa-4ab1-804a-a37dabca98c7 Caño Espinel, Manuela del 6ce25a8c-83b0-480e-80e9-3f75787c4b2d 600 Prokop, Andreas 9a0b885b-6bb5-4d4a-9274-4966cf6551aa Sánchez Soriano, Natalia dac4526d-e287-4a92-9a9f-757d1c0a53e7 600 2023-12-14T15:22:33Z 2023-12-14T15:22:33Z 2016 http://hdl.handle.net/10259/8206 10.7554/eLife.14694 2050-084X 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. This work was made possible through funding by the BBSRC (BB/M007456/1) to NSS, by the BBSRC (BB/I002448/1) and Wellcome Trust ISSF (105610/Z/14/Z) to AP, and the German Science Foundation (DFG; VO 2071/1-1) to AV. The Bioimaging Facility microscopes used in this study were purchased with grants from the BBSRC, The Wellcome Trust and the University of Manchester Strategic Fund, and the Manchester Fly Facility where flies were kept and genetic crosses performed has been supported by funds from The University of Manchester and the Wellcome Trust (087742/Z/08/Z). We thank Meredith Lees and Egor Zindy for experimental help, Bassem Hassan, Roland Brandt and Nigel Hooper for helpful comments on the manuscript, Thomas Schwarz, Sean Sweeney, Bassem Hassan, Nick Lowe and Talila Volk for kindly providing reagents. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were used in this study. application/pdf eng eLife Sciences Publications eLife. 2016, V. 5, e14694 http://dx.doi.org/10.7554/eLife.14694 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Biología Neurología Medicina Biology Neurology Medicine Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion eLife 5 THUMBNAIL Voelzmann-elife_2016.pdf.jpg Voelzmann-elife_2016.pdf.jpg IM Thumbnail image/jpeg 4983 https://riubu.ubu.es/bitstream/10259/8206/4/Voelzmann-elife_2016.pdf.jpg f64e4bec69e9493691994ee025605d42 MD5 4 LICENSE license.txt license.txt text/plain; charset=utf-8 1362 https://riubu.ubu.es/bitstream/10259/8206/3/license.txt 5d013bfa6e473ff0db22cd82a4d71a70 MD5 3 CC-LICENSE license_rdf license_rdf application/rdf+xml; charset=utf-8 908 https://riubu.ubu.es/bitstream/10259/8206/2/license_rdf 0175ea4a2d4caec4bbcc37e300941108 MD5 2 ORIGINAL Voelzmann-elife_2016.pdf Voelzmann-elife_2016.pdf application/pdf 11719285 https://riubu.ubu.es/bitstream/10259/8206/1/Voelzmann-elife_2016.pdf 8eec2a6d0fa45d8d84d1e1b1c96f2c2e MD5 1 10259/8206 oai:riubu.ubu.es:10259/8206 2023-12-15 02:05:25.366 Repositorio Institucional de la Universidad de Burgos bubrep@ubu.es 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