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Contribution of GTPase activity to LRRK2-associated Parkinson disease

Mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8, OMIM 607060) gene represent the most common known cause of hereditary Parkinson’s disease (PD) with late-onset and dominant inheritance. LRRK2 protein is composed of multiple domains including two distinct enzymatic domains, a kinase and a...

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Autores principales: Tsika, Elpida, Moore, Darren J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Landes Bioscience 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976973/
https://www.ncbi.nlm.nih.gov/pubmed/24025585
http://dx.doi.org/10.4161/sgtp.25130
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author Tsika, Elpida
Moore, Darren J
author_facet Tsika, Elpida
Moore, Darren J
author_sort Tsika, Elpida
collection PubMed
description Mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8, OMIM 607060) gene represent the most common known cause of hereditary Parkinson’s disease (PD) with late-onset and dominant inheritance. LRRK2 protein is composed of multiple domains including two distinct enzymatic domains, a kinase and a Ras-of-complex (Roc) GTPase, connected by a C-terminal-of-Roc (COR) domain, and belongs to the ROCO protein family. Disease-causing mutations located in the kinase domain enhance kinase activity (i.e., G2019S) whereas mutations clustering within the Roc-COR tandem domain impair GTPase activity (i.e., R1441C/G and Y1699C). Familial LRRK2 mutations commonly induce neuronal toxicity that, at least for the frequent G2019S variant, is dependent on kinase activity. The contribution of GTPase activity to LRRK2-dependent neuronal toxicity is not yet clear. Therefore, both GTPase and kinase activity may be important for mediating neurodegeneration in PD due to familial LRRK2 mutations. At present, the physiological function of LRRK2 in the mammalian brain and the regulation of its enzymatic activity are incompletely understood. In this review, we focus on the GTPase domain of LRRK2 and discuss the recent advances in elucidating its function and its interplay with the kinase domain for the regulation of LRRK2 activity and toxicity. GTPase activity is an important feature of LRRK2 biology and pathophysiology and represents an underexplored yet potentially tractable therapeutic target for treating LRRK2-associated PD.
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spelling pubmed-39769732014-04-07 Contribution of GTPase activity to LRRK2-associated Parkinson disease Tsika, Elpida Moore, Darren J Small GTPases Review Mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8, OMIM 607060) gene represent the most common known cause of hereditary Parkinson’s disease (PD) with late-onset and dominant inheritance. LRRK2 protein is composed of multiple domains including two distinct enzymatic domains, a kinase and a Ras-of-complex (Roc) GTPase, connected by a C-terminal-of-Roc (COR) domain, and belongs to the ROCO protein family. Disease-causing mutations located in the kinase domain enhance kinase activity (i.e., G2019S) whereas mutations clustering within the Roc-COR tandem domain impair GTPase activity (i.e., R1441C/G and Y1699C). Familial LRRK2 mutations commonly induce neuronal toxicity that, at least for the frequent G2019S variant, is dependent on kinase activity. The contribution of GTPase activity to LRRK2-dependent neuronal toxicity is not yet clear. Therefore, both GTPase and kinase activity may be important for mediating neurodegeneration in PD due to familial LRRK2 mutations. At present, the physiological function of LRRK2 in the mammalian brain and the regulation of its enzymatic activity are incompletely understood. In this review, we focus on the GTPase domain of LRRK2 and discuss the recent advances in elucidating its function and its interplay with the kinase domain for the regulation of LRRK2 activity and toxicity. GTPase activity is an important feature of LRRK2 biology and pathophysiology and represents an underexplored yet potentially tractable therapeutic target for treating LRRK2-associated PD. Landes Bioscience 2013-07-01 2013-06-10 /pmc/articles/PMC3976973/ /pubmed/24025585 http://dx.doi.org/10.4161/sgtp.25130 Text en Copyright © 2013 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Review
Tsika, Elpida
Moore, Darren J
Contribution of GTPase activity to LRRK2-associated Parkinson disease
title Contribution of GTPase activity to LRRK2-associated Parkinson disease
title_full Contribution of GTPase activity to LRRK2-associated Parkinson disease
title_fullStr Contribution of GTPase activity to LRRK2-associated Parkinson disease
title_full_unstemmed Contribution of GTPase activity to LRRK2-associated Parkinson disease
title_short Contribution of GTPase activity to LRRK2-associated Parkinson disease
title_sort contribution of gtpase activity to lrrk2-associated parkinson disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976973/
https://www.ncbi.nlm.nih.gov/pubmed/24025585
http://dx.doi.org/10.4161/sgtp.25130
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