Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10

Abstract Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinson’s disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential...

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Autores principales:	Xiang Wang, Elvira Negrou, Michael T. Maloney, Vitaliy V. Bondar, Shan V. Andrews, Manuel Montalban, Ceyda Llapashtica, Romeo Maciuca, Hoang Nguyen, Hilda Solanoy, Annie Arguello, Laralynne Przybyla, Nathan J. Moerke, Sarah Huntwork-Rodriguez, Anastasia G. Henry
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1aca3cf646994a96a51018658104a0b3
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spelling	oai:doaj.org-article:1aca3cf646994a96a51018658104a0b32021-12-02T17:23:16ZUnderstanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab1010.1038/s41598-021-91943-42045-2322https://doaj.org/article/1aca3cf646994a96a51018658104a0b32021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91943-4https://doaj.org/toc/2045-2322Abstract Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinson’s disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential of LRRK2 kinase inhibitors for PD. To better understand the role of LRRK2 in disease and to support the clinical development of LRRK2 inhibitors, quantitative and high-throughput assays to measure LRRK2 levels and activity are needed. We developed and applied such assays to measure the levels of LRRK2 as well as the phosphorylation of LRRK2 itself or one of its substrates, Rab10 (pT73 Rab10). We observed increased LRRK2 activity in various cellular models of disease, including iPSC-derived microglia, as well as in human subjects carrying the disease-linked variant LRRK2 G2019S. Capitalizing on the high-throughput and sensitive nature of these assays, we detected a significant reduction in LRRK2 activity in subjects carrying missense variants in LRRK2 associated with reduced disease risk. Finally, we optimized these assays to enable analysis of LRRK2 activity following inhibition in human peripheral blood mononuclear cells (PBMCs) and whole blood, demonstrating their potential utility as biomarkers to assess changes in LRRK2 expression and activity in the clinic.Xiang WangElvira NegrouMichael T. MaloneyVitaliy V. BondarShan V. AndrewsManuel MontalbanCeyda LlapashticaRomeo MaciucaHoang NguyenHilda SolanoyAnnie ArguelloLaralynne PrzybylaNathan J. MoerkeSarah Huntwork-RodriguezAnastasia G. HenryNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiang Wang Elvira Negrou Michael T. Maloney Vitaliy V. Bondar Shan V. Andrews Manuel Montalban Ceyda Llapashtica Romeo Maciuca Hoang Nguyen Hilda Solanoy Annie Arguello Laralynne Przybyla Nathan J. Moerke Sarah Huntwork-Rodriguez Anastasia G. Henry Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10
description	Abstract Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinson’s disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential of LRRK2 kinase inhibitors for PD. To better understand the role of LRRK2 in disease and to support the clinical development of LRRK2 inhibitors, quantitative and high-throughput assays to measure LRRK2 levels and activity are needed. We developed and applied such assays to measure the levels of LRRK2 as well as the phosphorylation of LRRK2 itself or one of its substrates, Rab10 (pT73 Rab10). We observed increased LRRK2 activity in various cellular models of disease, including iPSC-derived microglia, as well as in human subjects carrying the disease-linked variant LRRK2 G2019S. Capitalizing on the high-throughput and sensitive nature of these assays, we detected a significant reduction in LRRK2 activity in subjects carrying missense variants in LRRK2 associated with reduced disease risk. Finally, we optimized these assays to enable analysis of LRRK2 activity following inhibition in human peripheral blood mononuclear cells (PBMCs) and whole blood, demonstrating their potential utility as biomarkers to assess changes in LRRK2 expression and activity in the clinic.
format	article
author	Xiang Wang Elvira Negrou Michael T. Maloney Vitaliy V. Bondar Shan V. Andrews Manuel Montalban Ceyda Llapashtica Romeo Maciuca Hoang Nguyen Hilda Solanoy Annie Arguello Laralynne Przybyla Nathan J. Moerke Sarah Huntwork-Rodriguez Anastasia G. Henry
author_facet	Xiang Wang Elvira Negrou Michael T. Maloney Vitaliy V. Bondar Shan V. Andrews Manuel Montalban Ceyda Llapashtica Romeo Maciuca Hoang Nguyen Hilda Solanoy Annie Arguello Laralynne Przybyla Nathan J. Moerke Sarah Huntwork-Rodriguez Anastasia G. Henry
author_sort	Xiang Wang
title	Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10
title_short	Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10
title_full	Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10
title_fullStr	Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10
title_full_unstemmed	Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10
title_sort	understanding lrrk2 kinase activity in preclinical models and human subjects through quantitative analysis of lrrk2 and pt73 rab10
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1aca3cf646994a96a51018658104a0b3
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Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10

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