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No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts

Mutations within the LRRK2 gene have been identified in Parkinson’s disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human ce...

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Autores principales: Garcia-Miralles, Marta, Coomaraswamy, Janaky, Häbig, Karina, Herzig, Martin C., Funk, Natalja, Gillardon, Frank, Maisel, Martina, Jucker, Mathias, Gasser, Thomas, Galter, Dagmar, Biskup, Saskia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382199/
https://www.ncbi.nlm.nih.gov/pubmed/25830304
http://dx.doi.org/10.1371/journal.pone.0118947
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author Garcia-Miralles, Marta
Coomaraswamy, Janaky
Häbig, Karina
Herzig, Martin C.
Funk, Natalja
Gillardon, Frank
Maisel, Martina
Jucker, Mathias
Gasser, Thomas
Galter, Dagmar
Biskup, Saskia
author_facet Garcia-Miralles, Marta
Coomaraswamy, Janaky
Häbig, Karina
Herzig, Martin C.
Funk, Natalja
Gillardon, Frank
Maisel, Martina
Jucker, Mathias
Gasser, Thomas
Galter, Dagmar
Biskup, Saskia
author_sort Garcia-Miralles, Marta
collection PubMed
description Mutations within the LRRK2 gene have been identified in Parkinson’s disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel transgenic mouse model expressing physiological levels of human wild type and G2019S-mutant LRRK2. No neuronal loss or neurodegeneration was detected in midbrain dopamine neurons at the age of 12 months. Postnatal hippocampal neurons derived from transgenic mice showed no alterations in the seven parameters examined concerning neurite outgrowth sampled automatically on several hundred neurons using high content imaging. Treatment with the kinase inhibitor LRRK2-IN-1 resulted in no significant changes in the neurite outgrowth. In human fibroblasts we analyzed whether pathogenic LRRK2 mutations change cytoskeleton functions such as cell adhesion. To this end we compared the adhesion characteristics of human skin fibroblasts derived from six PD patients carrying one of three different pathogenic LRRK2 mutations and from four age-matched control individuals. The mutant LRRK2 variants as well as the inhibition of LRRK2 kinase activity did not reveal any significant cell adhesion differences in cultured fibroblasts. In summary, our results in both human and mouse cell systems suggest that neither the expression of wild type or mutant LRRK2, nor the inhibition of LRRK2 kinase activity affect neurite complexity and cellular adhesion.
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spelling pubmed-43821992015-04-09 No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts Garcia-Miralles, Marta Coomaraswamy, Janaky Häbig, Karina Herzig, Martin C. Funk, Natalja Gillardon, Frank Maisel, Martina Jucker, Mathias Gasser, Thomas Galter, Dagmar Biskup, Saskia PLoS One Research Article Mutations within the LRRK2 gene have been identified in Parkinson’s disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel transgenic mouse model expressing physiological levels of human wild type and G2019S-mutant LRRK2. No neuronal loss or neurodegeneration was detected in midbrain dopamine neurons at the age of 12 months. Postnatal hippocampal neurons derived from transgenic mice showed no alterations in the seven parameters examined concerning neurite outgrowth sampled automatically on several hundred neurons using high content imaging. Treatment with the kinase inhibitor LRRK2-IN-1 resulted in no significant changes in the neurite outgrowth. In human fibroblasts we analyzed whether pathogenic LRRK2 mutations change cytoskeleton functions such as cell adhesion. To this end we compared the adhesion characteristics of human skin fibroblasts derived from six PD patients carrying one of three different pathogenic LRRK2 mutations and from four age-matched control individuals. The mutant LRRK2 variants as well as the inhibition of LRRK2 kinase activity did not reveal any significant cell adhesion differences in cultured fibroblasts. In summary, our results in both human and mouse cell systems suggest that neither the expression of wild type or mutant LRRK2, nor the inhibition of LRRK2 kinase activity affect neurite complexity and cellular adhesion. Public Library of Science 2015-04-01 /pmc/articles/PMC4382199/ /pubmed/25830304 http://dx.doi.org/10.1371/journal.pone.0118947 Text en © 2015 Garcia-Miralles et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Garcia-Miralles, Marta
Coomaraswamy, Janaky
Häbig, Karina
Herzig, Martin C.
Funk, Natalja
Gillardon, Frank
Maisel, Martina
Jucker, Mathias
Gasser, Thomas
Galter, Dagmar
Biskup, Saskia
No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts
title No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts
title_full No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts
title_fullStr No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts
title_full_unstemmed No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts
title_short No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts
title_sort no dopamine cell loss or changes in cytoskeleton function in transgenic mice expressing physiological levels of wild type or g2019s mutant lrrk2 and in human fibroblasts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382199/
https://www.ncbi.nlm.nih.gov/pubmed/25830304
http://dx.doi.org/10.1371/journal.pone.0118947
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