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Physiological and pathological functions of LRRK2: implications from substrate proteins

Leucine-rich repeat kinase 2 (LRRK2) encodes a 2527-amino acid (aa) protein composed of multiple functional domains, including a Ras of complex proteins (ROC)-type GTP-binding domain, a carboxyl terminal of ROC (COR) domain, a serine/threonine protein kinase domain, and several repeat domains. LRRK2...

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Detalles Bibliográficos
Autores principales: Araki, Miho, Ito, Genta, Tomita, Taisuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373236/
https://www.ncbi.nlm.nih.gov/pubmed/32714591
http://dx.doi.org/10.1042/NS20180005
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author Araki, Miho
Ito, Genta
Tomita, Taisuke
author_facet Araki, Miho
Ito, Genta
Tomita, Taisuke
author_sort Araki, Miho
collection PubMed
description Leucine-rich repeat kinase 2 (LRRK2) encodes a 2527-amino acid (aa) protein composed of multiple functional domains, including a Ras of complex proteins (ROC)-type GTP-binding domain, a carboxyl terminal of ROC (COR) domain, a serine/threonine protein kinase domain, and several repeat domains. LRRK2 is genetically involved in the pathogenesis of both sporadic and familial Parkinson’s disease (FPD). Parkinson’s disease (PD) is the second most common neurodegenerative disorder, manifesting progressive motor dysfunction. PD is pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and the presence of intracellular inclusion bodies called Lewy bodies (LB) in the remaining neurons. As the most frequent PD-causing mutation in LRRK2, G2019S, increases the kinase activity of LRRK2, an abnormal increase in LRRK2 kinase activity is believed to contribute to PD pathology; however, the precise biological functions of LRRK2 involved in PD pathogenesis remain unknown. Although biochemical studies have discovered several substrate proteins of LRRK2 including Rab GTPases and tau, little is known about whether excess phosphorylation of these substrates is the cause of the neurodegeneration in PD. In this review, we summarize latest findings regarding the physiological and pathological functions of LRRK2, and discuss the possible molecular mechanisms of neurodegeneration caused by LRRK2 and its substrates.
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spelling pubmed-73732362020-07-23 Physiological and pathological functions of LRRK2: implications from substrate proteins Araki, Miho Ito, Genta Tomita, Taisuke Neuronal Signal Aging Leucine-rich repeat kinase 2 (LRRK2) encodes a 2527-amino acid (aa) protein composed of multiple functional domains, including a Ras of complex proteins (ROC)-type GTP-binding domain, a carboxyl terminal of ROC (COR) domain, a serine/threonine protein kinase domain, and several repeat domains. LRRK2 is genetically involved in the pathogenesis of both sporadic and familial Parkinson’s disease (FPD). Parkinson’s disease (PD) is the second most common neurodegenerative disorder, manifesting progressive motor dysfunction. PD is pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and the presence of intracellular inclusion bodies called Lewy bodies (LB) in the remaining neurons. As the most frequent PD-causing mutation in LRRK2, G2019S, increases the kinase activity of LRRK2, an abnormal increase in LRRK2 kinase activity is believed to contribute to PD pathology; however, the precise biological functions of LRRK2 involved in PD pathogenesis remain unknown. Although biochemical studies have discovered several substrate proteins of LRRK2 including Rab GTPases and tau, little is known about whether excess phosphorylation of these substrates is the cause of the neurodegeneration in PD. In this review, we summarize latest findings regarding the physiological and pathological functions of LRRK2, and discuss the possible molecular mechanisms of neurodegeneration caused by LRRK2 and its substrates. Portland Press Ltd. 2018-10-10 /pmc/articles/PMC7373236/ /pubmed/32714591 http://dx.doi.org/10.1042/NS20180005 Text en © 2018 The Author(s). https://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
spellingShingle Aging
Araki, Miho
Ito, Genta
Tomita, Taisuke
Physiological and pathological functions of LRRK2: implications from substrate proteins
title Physiological and pathological functions of LRRK2: implications from substrate proteins
title_full Physiological and pathological functions of LRRK2: implications from substrate proteins
title_fullStr Physiological and pathological functions of LRRK2: implications from substrate proteins
title_full_unstemmed Physiological and pathological functions of LRRK2: implications from substrate proteins
title_short Physiological and pathological functions of LRRK2: implications from substrate proteins
title_sort physiological and pathological functions of lrrk2: implications from substrate proteins
topic Aging
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373236/
https://www.ncbi.nlm.nih.gov/pubmed/32714591
http://dx.doi.org/10.1042/NS20180005
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