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High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain
The G2019S mutation in the multidomain protein leucine-rich repeat kinase 2 (LRRK2) is one of the most frequently identified genetic causes of Parkinson’s disease (PD). Clinically, LRRK2(G2019S) carriers with PD and idiopathic PD patients have a very similar disease with brainstem and cortical Lewy...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352901/ https://www.ncbi.nlm.nih.gov/pubmed/22615783 http://dx.doi.org/10.1371/journal.pone.0036581 |
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author | Herzig, Martin C. Bidinosti, Michael Schweizer, Tatjana Hafner, Thomas Stemmelen, Christine Weiss, Andreas Danner, Simone Vidotto, Nella Stauffer, Daniela Barske, Carmen Mayer, Franziska Schmid, Peter Rovelli, Giorgio van der Putten, P. Herman Shimshek, Derya R. |
author_facet | Herzig, Martin C. Bidinosti, Michael Schweizer, Tatjana Hafner, Thomas Stemmelen, Christine Weiss, Andreas Danner, Simone Vidotto, Nella Stauffer, Daniela Barske, Carmen Mayer, Franziska Schmid, Peter Rovelli, Giorgio van der Putten, P. Herman Shimshek, Derya R. |
author_sort | Herzig, Martin C. |
collection | PubMed |
description | The G2019S mutation in the multidomain protein leucine-rich repeat kinase 2 (LRRK2) is one of the most frequently identified genetic causes of Parkinson’s disease (PD). Clinically, LRRK2(G2019S) carriers with PD and idiopathic PD patients have a very similar disease with brainstem and cortical Lewy pathology (α-synucleinopathy) as histopathological hallmarks. Some patients have Tau pathology. Enhanced kinase function of the LRRK2(G2019S) mutant protein is a prime suspect mechanism for carriers to develop PD but observations in LRRK2 knock-out, G2019S knock-in and kinase-dead mutant mice suggest that LRRK2 steady-state abundance of the protein also plays a determining role. One critical question concerning the molecular pathogenesis in LRRK2(G2019S) PD patients is whether α-synuclein (aSN) has a contributory role. To this end we generated mice with high expression of either wildtype or G2019S mutant LRRK2 in brainstem and cortical neurons. High levels of these LRRK2 variants left endogenous aSN and Tau levels unaltered and did not exacerbate or otherwise modify α-synucleinopathy in mice that co-expressed high levels of LRRK2 and aSN in brain neurons. On the contrary, in some lines high LRRK2 levels improved motor skills in the presence and absence of aSN-transgene-induced disease. Therefore, in many neurons high LRRK2 levels are well tolerated and not sufficient to drive or exacerbate neuronal α-synucleinopathy. |
format | Online Article Text |
id | pubmed-3352901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33529012012-05-21 High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain Herzig, Martin C. Bidinosti, Michael Schweizer, Tatjana Hafner, Thomas Stemmelen, Christine Weiss, Andreas Danner, Simone Vidotto, Nella Stauffer, Daniela Barske, Carmen Mayer, Franziska Schmid, Peter Rovelli, Giorgio van der Putten, P. Herman Shimshek, Derya R. PLoS One Research Article The G2019S mutation in the multidomain protein leucine-rich repeat kinase 2 (LRRK2) is one of the most frequently identified genetic causes of Parkinson’s disease (PD). Clinically, LRRK2(G2019S) carriers with PD and idiopathic PD patients have a very similar disease with brainstem and cortical Lewy pathology (α-synucleinopathy) as histopathological hallmarks. Some patients have Tau pathology. Enhanced kinase function of the LRRK2(G2019S) mutant protein is a prime suspect mechanism for carriers to develop PD but observations in LRRK2 knock-out, G2019S knock-in and kinase-dead mutant mice suggest that LRRK2 steady-state abundance of the protein also plays a determining role. One critical question concerning the molecular pathogenesis in LRRK2(G2019S) PD patients is whether α-synuclein (aSN) has a contributory role. To this end we generated mice with high expression of either wildtype or G2019S mutant LRRK2 in brainstem and cortical neurons. High levels of these LRRK2 variants left endogenous aSN and Tau levels unaltered and did not exacerbate or otherwise modify α-synucleinopathy in mice that co-expressed high levels of LRRK2 and aSN in brain neurons. On the contrary, in some lines high LRRK2 levels improved motor skills in the presence and absence of aSN-transgene-induced disease. Therefore, in many neurons high LRRK2 levels are well tolerated and not sufficient to drive or exacerbate neuronal α-synucleinopathy. Public Library of Science 2012-05-15 /pmc/articles/PMC3352901/ /pubmed/22615783 http://dx.doi.org/10.1371/journal.pone.0036581 Text en Herzig 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 Herzig, Martin C. Bidinosti, Michael Schweizer, Tatjana Hafner, Thomas Stemmelen, Christine Weiss, Andreas Danner, Simone Vidotto, Nella Stauffer, Daniela Barske, Carmen Mayer, Franziska Schmid, Peter Rovelli, Giorgio van der Putten, P. Herman Shimshek, Derya R. High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain |
title | High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain |
title_full | High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain |
title_fullStr | High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain |
title_full_unstemmed | High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain |
title_short | High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain |
title_sort | high lrrk2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352901/ https://www.ncbi.nlm.nih.gov/pubmed/22615783 http://dx.doi.org/10.1371/journal.pone.0036581 |
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