The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions

Abstract Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson’s disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attr...

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Autores principales:	Maria Dolores Perez Carrion, Silvia Marsicano, Federica Daniele, Antonella Marte, Francesca Pischedda, Eliana Di Cairano, Ester Piovesana, Felix von Zweydorf, Elisabeth Kremmer, Christian Johannes Gloeckner, Franco Onofri, Carla Perego, Giovanni Piccoli
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/80d9facf1fc1460aa75b5282c4e64bdf
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spelling	oai:doaj.org-article:80d9facf1fc1460aa75b5282c4e64bdf2021-12-02T11:52:55ZThe LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions10.1038/s41598-017-05760-92045-2322https://doaj.org/article/80d9facf1fc1460aa75b5282c4e64bdf2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05760-9https://doaj.org/toc/2045-2322Abstract Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson’s disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely β3-Cav2.1 at N-terminus part and β-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause disease.Maria Dolores Perez CarrionSilvia MarsicanoFederica DanieleAntonella MarteFrancesca PischeddaEliana Di CairanoEster PiovesanaFelix von ZweydorfElisabeth KremmerChristian Johannes GloecknerFranco OnofriCarla PeregoGiovanni PiccoliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria Dolores Perez Carrion Silvia Marsicano Federica Daniele Antonella Marte Francesca Pischedda Eliana Di Cairano Ester Piovesana Felix von Zweydorf Elisabeth Kremmer Christian Johannes Gloeckner Franco Onofri Carla Perego Giovanni Piccoli The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions
description	Abstract Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson’s disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely β3-Cav2.1 at N-terminus part and β-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause disease.
format	article
author	Maria Dolores Perez Carrion Silvia Marsicano Federica Daniele Antonella Marte Francesca Pischedda Eliana Di Cairano Ester Piovesana Felix von Zweydorf Elisabeth Kremmer Christian Johannes Gloeckner Franco Onofri Carla Perego Giovanni Piccoli
author_facet	Maria Dolores Perez Carrion Silvia Marsicano Federica Daniele Antonella Marte Francesca Pischedda Eliana Di Cairano Ester Piovesana Felix von Zweydorf Elisabeth Kremmer Christian Johannes Gloeckner Franco Onofri Carla Perego Giovanni Piccoli
author_sort	Maria Dolores Perez Carrion
title	The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions
title_short	The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions
title_full	The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions
title_fullStr	The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions
title_full_unstemmed	The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions
title_sort	lrrk2 g2385r variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/80d9facf1fc1460aa75b5282c4e64bdf
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The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions

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