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R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations
LRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered stria...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9649688/ https://www.ncbi.nlm.nih.gov/pubmed/36357506 http://dx.doi.org/10.1038/s42003-022-04136-8 |
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author | Xenias, Harry S. Chen, Chuyu Kang, Shuo Cherian, Suraj Situ, Xiaolei Shanmugasundaram, Bharanidharan Liu, Guoxiang Scesa, Giuseppe Savio Chan, C. Parisiadou, Loukia |
author_facet | Xenias, Harry S. Chen, Chuyu Kang, Shuo Cherian, Suraj Situ, Xiaolei Shanmugasundaram, Bharanidharan Liu, Guoxiang Scesa, Giuseppe Savio Chan, C. Parisiadou, Loukia |
author_sort | Xenias, Harry S. |
collection | PubMed |
description | LRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations’ impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients. |
format | Online Article Text |
id | pubmed-9649688 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96496882022-11-15 R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations Xenias, Harry S. Chen, Chuyu Kang, Shuo Cherian, Suraj Situ, Xiaolei Shanmugasundaram, Bharanidharan Liu, Guoxiang Scesa, Giuseppe Savio Chan, C. Parisiadou, Loukia Commun Biol Article LRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations’ impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients. Nature Publishing Group UK 2022-11-10 /pmc/articles/PMC9649688/ /pubmed/36357506 http://dx.doi.org/10.1038/s42003-022-04136-8 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Xenias, Harry S. Chen, Chuyu Kang, Shuo Cherian, Suraj Situ, Xiaolei Shanmugasundaram, Bharanidharan Liu, Guoxiang Scesa, Giuseppe Savio Chan, C. Parisiadou, Loukia R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations |
title | R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations |
title_full | R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations |
title_fullStr | R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations |
title_full_unstemmed | R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations |
title_short | R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations |
title_sort | r1441c and g2019s lrrk2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9649688/ https://www.ncbi.nlm.nih.gov/pubmed/36357506 http://dx.doi.org/10.1038/s42003-022-04136-8 |
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