Increased endosomal microautophagy reduces Tau driven synaptic dysfunction.

Event Abstract Back to Event Increased endosomal microautophagy reduces Tau driven synaptic dysfunction. Valerie Uytterhoeven1*, Liesbeth Deaulmerie1 and Patrik Verstreken1 1 VIB & KU Leuven Center for Brain & Disease Research, Belgium Valerie Uytterhoeven, Liesbeth Deaulmerie, Patrik Verstreken VIB-KU Leuven Center for Brain and Disease Research 3000, Leuven, Belgium Most of the drug discovery efforts in AD have been focused on Aß removal but these studies have been unsuccessful in phase 3 clinical trials. Therefore, there is an urgent need to fill the therapeutic pipeline with new innovative targets in dementia. Targeting Tau is emerging as a new and exciting possibility as Tau is a major mediator of neurodegeneration. Tau tangles are present in the brains of AD patients but also several other neurodegenerative diseases and strategies that remove Tau oligomers and Tau tangles are tested in clinical trials. These anti-Tau drugs may keep misfolded Tau from spreading and damaging additional neurons, but they may be inefficient at targeting soluble Tau early in the disease before tangles are formed and thus be relatively late to spare cognitive defects. Our approach is therefore refreshing as it tackles a different aspect of Tau induced dysfunction. We have shown in Drosophila that endosomal microautophagy is functional at presynapses and regulates the turnover of proteins harboring pentapeptide motifs, biochemically related to the KFERQ sequence. The chaperone, Hsc70-4 recognizes proteins with such a motif and regulates their turnover by the engulfment of these proteins in the multivesicular bodies/late endosomes via inducing membrane bending (Uytterhoeven, 2015). Intriguingly, Tau harbors two such motifs and we tested if increasing Hsc70 levels has an effect on Tau levels and its pathogenic function. Indeed, increasing microautophagy reduces mutant Tau levels and synaptic vesicles sequestration at the presynapse, two phenotypes previously shown by our lab to appear after expressing mutant Tau in the nervous system of the fly (Zhou et al. ,2017 and McInnes et al., 2018). We will further test if increasing microautophagy levels is able to rescue Tau associated neurodegeneration in the fly brain. In addition, we are generating tools to increase microautophagy levels in human neurons and test the effect on Tau pathology of human neurons harboring pathogenic Tau mutations. Together, our work provides important insight into the contribution of microautophagy on Tau-induced disease onset and progression and the knowledge of these molecular mechanisms allows the development of methods/treatments to alleviate defects in dementia. References Valerie Uytterhoeven, Elsa Lauwers, Ine Maes, Katarzyna Miskiewicz, Nuno M Melo, Jef Swerts, Sabine Kuenen, Rafael Wittocx, Nikky Corthout, Siewert-Jan Marrink, Sebastian Munck and Patrik Verstreken (2015). Hsc70-4 Deforms Membranes to Promote Synaptic Protein Turnover by Endosomal Microautophagy. Neuron. 88: 735-748. PMID: 26590345. Lujia Zhou, Joseph McInnes, Keimpe Wierda, Matthew Holt, Abigail G. Herrmann, Rosemary J. Jackson, Yu-Chun Wang, Jef Swerts, Jelle Beyens, Katarzyna Miskiewicz, Sven Vilain, Ilse Dewachter, Diederik Moechars, Bart De Strooper, Tara L. Spires-Jones, Joris De Wit and Patrik Verstreken (2016 ). Tau association with synaptic vesicles causes presynaptic dysfunction. Nature Communications. 8: 15295. PMID: 28492240. Joseph McInnes, Keimpe Wierda, An Snellinx, Laura Bounti, Yu-Chun Wang, Llie-Cosmin Stancu, Nuno Apostolo, Kris Gevaert, Ilse Dewachter, Tara L. Spires-Jones, Bart De Strooper, Joris De wit, Lujia Zhou and Patrik Verstreken (2018). Synaptogyrin-3 mediates presynaptic dysfunction induced by Tau. Neuron. 97: 823-835. PMID: 29398363 Keywords: tau, HSPA8, Microautophagy, Human stem cell, Drosophila, Hsc70-4 Conference: Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018. Presentation Type: e-posters Topic: NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE Citation: Uytterhoeven V, Deaulmerie L and Verstreken P (2019). Increased endosomal microautophagy reduces Tau driven synaptic dysfunction.. Front. Neurosci. Conference Abstract: Belgian Brain Congress 2018 — Belgian Brain Council. doi: 10.3389/conf.fnins.2018.95.00102 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 31 Aug 2018; Published Online: 17 Jan 2019. * Correspondence: Dr. Valerie Uytterhoeven, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium, valerie.uytterhoeven@kuleuven.vib.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Valerie Uytterhoeven Liesbeth Deaulmerie Patrik Verstreken Google Valerie Uytterhoeven Liesbeth Deaulmerie Patrik Verstreken Google Scholar Valerie Uytterhoeven Liesbeth Deaulmerie Patrik Verstreken PubMed Valerie Uytterhoeven Liesbeth Deaulmerie Patrik Verstreken Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.