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LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction

Parkinson's disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here w...

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Autores principales: Penney, Jay, Tsurudome, Kazuya, Liao, Edward H., Kauwe, Grant, Gray, Lindsay, Yanagiya, Akiko, R. Calderon, Mario, Sonenberg, Nahum, Haghighi, A. Pejmun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960312/
https://www.ncbi.nlm.nih.gov/pubmed/27432119
http://dx.doi.org/10.1038/ncomms12188
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author Penney, Jay
Tsurudome, Kazuya
Liao, Edward H.
Kauwe, Grant
Gray, Lindsay
Yanagiya, Akiko
R. Calderon, Mario
Sonenberg, Nahum
Haghighi, A. Pejmun
author_facet Penney, Jay
Tsurudome, Kazuya
Liao, Edward H.
Kauwe, Grant
Gray, Lindsay
Yanagiya, Akiko
R. Calderon, Mario
Sonenberg, Nahum
Haghighi, A. Pejmun
author_sort Penney, Jay
collection PubMed
description Parkinson's disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here we demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. Conversely, postsynaptic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of presynaptic neurotransmitter release by increasing the size of the release ready pool of vesicles. We show that LRRK2 promotes cap-dependent translation and identify Furin 1 as its translational target, which is required for the synaptic function of LRRK2. As the regulation of synaptic homeostasis plays a fundamental role in ensuring normal and stable synaptic function, our findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits.
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spelling pubmed-49603122016-09-06 LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction Penney, Jay Tsurudome, Kazuya Liao, Edward H. Kauwe, Grant Gray, Lindsay Yanagiya, Akiko R. Calderon, Mario Sonenberg, Nahum Haghighi, A. Pejmun Nat Commun Article Parkinson's disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here we demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. Conversely, postsynaptic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of presynaptic neurotransmitter release by increasing the size of the release ready pool of vesicles. We show that LRRK2 promotes cap-dependent translation and identify Furin 1 as its translational target, which is required for the synaptic function of LRRK2. As the regulation of synaptic homeostasis plays a fundamental role in ensuring normal and stable synaptic function, our findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits. Nature Publishing Group 2016-07-19 /pmc/articles/PMC4960312/ /pubmed/27432119 http://dx.doi.org/10.1038/ncomms12188 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Penney, Jay
Tsurudome, Kazuya
Liao, Edward H.
Kauwe, Grant
Gray, Lindsay
Yanagiya, Akiko
R. Calderon, Mario
Sonenberg, Nahum
Haghighi, A. Pejmun
LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
title LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
title_full LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
title_fullStr LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
title_full_unstemmed LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
title_short LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
title_sort lrrk2 regulates retrograde synaptic compensation at the drosophila neuromuscular junction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960312/
https://www.ncbi.nlm.nih.gov/pubmed/27432119
http://dx.doi.org/10.1038/ncomms12188
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