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Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease

View ORCID ProfileIovino Ludovica, View ORCID ProfileGiusti Veronica, View ORCID ProfilePischedda Francesca, View ORCID ProfileGiusto Elena, View ORCID ProfilePlotegher Nicoletta, View ORCID ProfileMarte Antonella, Battisti Ilaria, Di Iacovo Angela, View ORCID ProfileMarku Algerta, View ORCID ProfilePiccoli Giovanni, View ORCID ProfileBandopadhyay Rina, View ORCID ProfilePerego Carla, View ORCID ProfileBonifacino Tiziana, View ORCID ProfileBonanno Giambattista, View ORCID ProfileRoseti Cristina, View ORCID ProfileBossi Elena, View ORCID ProfileArrigoni Giorgio, View ORCID ProfileBubacco Luigi, View ORCID ProfileGreggio Elisa, View ORCID ProfileHilfiker Sabine, View ORCID ProfileCiviero Laura
doi: https://doi.org/10.1101/2021.08.04.455053
Iovino Ludovica
1Department of Biology, University of Padova, Italy
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Giusti Veronica
1Department of Biology, University of Padova, Italy
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Pischedda Francesca
2University of Trento, Department of Cellular, Computational and Integrative Biology – CIBIO, Trento, Italy
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Giusto Elena
3IRCCS San Camillo Hospital, Venice, Italy
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Plotegher Nicoletta
1Department of Biology, University of Padova, Italy
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Marte Antonella
4University of Genova, Department of Experimental Medicine, Genova, Italy;
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Battisti Ilaria
5Department of Biomedical Sciences, University of Padova, Padua, Italy
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Di Iacovo Angela
6Department of Biotechnology and Life Sciences, Center for Research in Neuroscience, University of Insubria, Varese
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Marku Algerta
7University of Milano, Department of Pharmacological and Biomolecular Sciences, Milano, Italy;
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Piccoli Giovanni
2University of Trento, Department of Cellular, Computational and Integrative Biology – CIBIO, Trento, Italy
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Bandopadhyay Rina
8Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, United Kingdom;
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Perego Carla
7University of Milano, Department of Pharmacological and Biomolecular Sciences, Milano, Italy;
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Bonifacino Tiziana
9University of Genova, Department of Pharmacy-DIFAR, Genoa, Italy
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Bonanno Giambattista
9University of Genova, Department of Pharmacy-DIFAR, Genoa, Italy
10IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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Roseti Cristina
6Department of Biotechnology and Life Sciences, Center for Research in Neuroscience, University of Insubria, Varese
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Bossi Elena
6Department of Biotechnology and Life Sciences, Center for Research in Neuroscience, University of Insubria, Varese
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Arrigoni Giorgio
5Department of Biomedical Sciences, University of Padova, Padua, Italy
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Bubacco Luigi
1Department of Biology, University of Padova, Italy
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Greggio Elisa
1Department of Biology, University of Padova, Italy
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Hilfiker Sabine
11Rutgers New Jersey Medical School, Department of Anesthesiology and Department of Physiology, Pharmacology and Neuroscience, Newark, New Jersey, United States of America;
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Civiero Laura
1Department of Biology, University of Padova, Italy
3IRCCS San Camillo Hospital, Venice, Italy
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  • ORCID record for Civiero Laura
  • For correspondence: laura.civiero@unipd.it
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Abstract

The Excitatory Amino Acid Transporter 2 (EAAT2) accounts for 80 % of brain glutamate clearance and is mainly expressed in astrocytic perisynaptic processes. EAAT2 function is finely regulated by endocytic events, recycling to the plasma membrane and degradation. Noteworthy, deficits in EAAT2 have been associated with neuronal excitotoxicity and neurodegeneration. In this study, we show that EAAT2 trafficking is impaired by the leucine-rich repeat kinase 2 (LRRK2) pathogenic variant G2019S, a common cause of late-onset familial Parkinson’s disease (PD). In LRRK2 G2019S human brains and experimental animal models, EAAT2 protein levels are significantly decreased, which is associated with elevated gliosis. The decreased expression of the transporter correlates with its reduced functionality in mouse LRRK2 G2019S purified astrocytic terminals and in Xenopus laevis oocytes expressing human LRRK2 G2019S. In Lrrk2 G2019S knockin mouse brain, the correct surface localization of the endogenous transporter is impaired, resulting in its interaction with a plethora of endo-vesicular proteins. Mechanistically, we report that pathogenic LRRK2 kinase activity delays the recycling of the transporter to the plasma membrane, causing its intracellular relocalization and degradation. Taken together, our results demonstrate that pathogenic LRRK2 interferes with the physiology of EAAT2, pointing to extracellular glutamate overload as a possible contributor to neurodegeneration in PD.

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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Posted August 05, 2021.
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Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease
Iovino Ludovica, Giusti Veronica, Pischedda Francesca, Giusto Elena, Plotegher Nicoletta, Marte Antonella, Battisti Ilaria, Di Iacovo Angela, Marku Algerta, Piccoli Giovanni, Bandopadhyay Rina, Perego Carla, Bonifacino Tiziana, Bonanno Giambattista, Roseti Cristina, Bossi Elena, Arrigoni Giorgio, Bubacco Luigi, Greggio Elisa, Hilfiker Sabine, Civiero Laura
bioRxiv 2021.08.04.455053; doi: https://doi.org/10.1101/2021.08.04.455053
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Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease
Iovino Ludovica, Giusti Veronica, Pischedda Francesca, Giusto Elena, Plotegher Nicoletta, Marte Antonella, Battisti Ilaria, Di Iacovo Angela, Marku Algerta, Piccoli Giovanni, Bandopadhyay Rina, Perego Carla, Bonifacino Tiziana, Bonanno Giambattista, Roseti Cristina, Bossi Elena, Arrigoni Giorgio, Bubacco Luigi, Greggio Elisa, Hilfiker Sabine, Civiero Laura
bioRxiv 2021.08.04.455053; doi: https://doi.org/10.1101/2021.08.04.455053

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