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Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer’s disease

Leticia Peris, Xiaoyi Qu, Jean-Marc Soleilhac, Julie Parato, Fabien Lanté, Atul Kumar, Maria Elena Pero, José Martínez-Hernández, Charlotte Corrao, Giulia Falivelli, Floriane Payet, Sylvie Gory-Fauré, Christophe Bosc, Marian Blanca Ramírez, Andrew Sproul, Jacques Brocard, Benjamin Di Cara, Philippe Delagrange, Alain Buisson, Yves Goldberg, Marie-Jo Moutin, Francesca Bartolini, Annie Andrieux
doi: https://doi.org/10.1101/2021.05.17.443847
Leticia Peris
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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  • For correspondence: leticia.peris@univ-grenoble-alpes.fr moutinm@univ-grenoble-alpes.fr fb2131@cumc.columbia.edu annie.andrieux@univ-grenoble-alpes.fr
Xiaoyi Qu
2Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168(th) Street, New York, NY 10032, USA
3Genentech, San Francisco, CA 94080, USA
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Jean-Marc Soleilhac
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Julie Parato
2Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168(th) Street, New York, NY 10032, USA
4Department of Natural Sciences, SUNY ESC, 177 Livingston St 6th Floor, Brooklyn, NY 11201
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Fabien Lanté
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Atul Kumar
2Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168(th) Street, New York, NY 10032, USA
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Maria Elena Pero
2Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168(th) Street, New York, NY 10032, USA
5Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137, Naples, Italy
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José Martínez-Hernández
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
6Synaptic Structure Laboratory, Dept. Ciencias Médicas, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Facultad de Medicina, Universidad Castilla-La Mancha, 02008 Albacete, Spain
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Charlotte Corrao
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Giulia Falivelli
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Floriane Payet
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Sylvie Gory-Fauré
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Christophe Bosc
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Marian Blanca Ramírez
2Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168(th) Street, New York, NY 10032, USA
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Andrew Sproul
2Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168(th) Street, New York, NY 10032, USA
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Jacques Brocard
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Benjamin Di Cara
7Institut de Recherche Servier, Croissy, France
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Philippe Delagrange
7Institut de Recherche Servier, Croissy, France
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Alain Buisson
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Yves Goldberg
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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Marie-Jo Moutin
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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  • For correspondence: leticia.peris@univ-grenoble-alpes.fr moutinm@univ-grenoble-alpes.fr fb2131@cumc.columbia.edu annie.andrieux@univ-grenoble-alpes.fr
Francesca Bartolini
2Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168(th) Street, New York, NY 10032, USA
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  • For correspondence: leticia.peris@univ-grenoble-alpes.fr moutinm@univ-grenoble-alpes.fr fb2131@cumc.columbia.edu annie.andrieux@univ-grenoble-alpes.fr
Annie Andrieux
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France
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  • For correspondence: leticia.peris@univ-grenoble-alpes.fr moutinm@univ-grenoble-alpes.fr fb2131@cumc.columbia.edu annie.andrieux@univ-grenoble-alpes.fr
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SUMMARY

In neurons, dynamic microtubules play regulatory roles in neurotransmission and synaptic plasticity. While stable microtubules contain detyrosinated tubulin, dynamic microtubules are composed of tyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination (Tyr/deTyr) cycle modulates microtubule dynamics and synaptic function. In the Tyr/deTyr cycle, the C-terminal tyrosine of α-tubulin is re-added by tubulin-tyrosine-ligase (TTL). Here we show that TTL+/− mice exhibit decreased tyrosinated microtubules, synaptic plasticity and memory deficits, and that reduced TTL expression is a feature of sporadic and familial Alzheimer’s disease (AD), with human APPV717I neurons having less dynamic microtubules. We find that spines visited by dynamic microtubules are more resistant to Amyloidβ1-42 and that TTL, by promoting microtubule entry into spines, prevents Aβ1-42-induced spine pruning. Our results demonstrate that the Tyr/deTyr cycle regulates synaptic plasticity, is protective against spine injury, and that tubulin re-tyrosination is lost in AD, providing evidence that a defective Tyr/deTyr cycle may contribute to neurodegeneration.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer’s disease
Leticia Peris, Xiaoyi Qu, Jean-Marc Soleilhac, Julie Parato, Fabien Lanté, Atul Kumar, Maria Elena Pero, José Martínez-Hernández, Charlotte Corrao, Giulia Falivelli, Floriane Payet, Sylvie Gory-Fauré, Christophe Bosc, Marian Blanca Ramírez, Andrew Sproul, Jacques Brocard, Benjamin Di Cara, Philippe Delagrange, Alain Buisson, Yves Goldberg, Marie-Jo Moutin, Francesca Bartolini, Annie Andrieux
bioRxiv 2021.05.17.443847; doi: https://doi.org/10.1101/2021.05.17.443847
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Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer’s disease
Leticia Peris, Xiaoyi Qu, Jean-Marc Soleilhac, Julie Parato, Fabien Lanté, Atul Kumar, Maria Elena Pero, José Martínez-Hernández, Charlotte Corrao, Giulia Falivelli, Floriane Payet, Sylvie Gory-Fauré, Christophe Bosc, Marian Blanca Ramírez, Andrew Sproul, Jacques Brocard, Benjamin Di Cara, Philippe Delagrange, Alain Buisson, Yves Goldberg, Marie-Jo Moutin, Francesca Bartolini, Annie Andrieux
bioRxiv 2021.05.17.443847; doi: https://doi.org/10.1101/2021.05.17.443847

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