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“LRRK2: Autophagy and Lysosomal Activity”

It has been 15 years since the Leucine-rich repeat kinase 2 (LRRK2) gene was identified as the most common genetic cause for Parkinson’s disease (PD). The two most common mutations are the LRRK2-G2019S, located in the kinase domain, and the LRRK2-R1441C, located in the ROC-COR domain. While the LRRK...

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Autores principales: Madureira, Marta, Connor-Robson, Natalie, Wade-Martins, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262160/
https://www.ncbi.nlm.nih.gov/pubmed/32523507
http://dx.doi.org/10.3389/fnins.2020.00498
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author Madureira, Marta
Connor-Robson, Natalie
Wade-Martins, Richard
author_facet Madureira, Marta
Connor-Robson, Natalie
Wade-Martins, Richard
author_sort Madureira, Marta
collection PubMed
description It has been 15 years since the Leucine-rich repeat kinase 2 (LRRK2) gene was identified as the most common genetic cause for Parkinson’s disease (PD). The two most common mutations are the LRRK2-G2019S, located in the kinase domain, and the LRRK2-R1441C, located in the ROC-COR domain. While the LRRK2-G2019S mutation is associated with increased kinase activity, the LRRK2-R1441C exhibits a decreased GTPase activity and altered kinase activity. Multiple lines of evidence have linked the LRRK2 protein with a role in the autophagy pathway and with lysosomal activity in neurons. Neurons rely heavily on autophagy to recycle proteins and process cellular waste due to their post-mitotic state. Additionally, lysosomal activity decreases with age which can potentiate the accumulation of α-synuclein, the pathological hallmark of PD, and subsequently lead to the build-up of Lewy bodies (LBs) observed in this disorder. This review provides an up to date summary of the LRRK2 field to understand its physiological role in the autophagy pathway in neurons and related cells. Careful assessment of how LRRK2 participates in the regulation of phagophore and autophagosome formation, autophagosome and lysosome fusion, lysosomal maturation, maintenance of lysosomal pH and calcium levels, and lysosomal protein degradation are addressed. The autophagy pathway is a complex cellular process and due to the variety of LRRK2 models studied in the field, associated phenotypes have been reported to be seemingly conflicting. This review provides an in-depth discussion of different models to assess the normal and disease-associated role of the LRRK2 protein on autophagic function. Given the importance of the autophagy pathway in Parkinson’s pathogenesis it is particularly relevant to focus on the role of LRRK2 to discover novel therapeutic approaches that restore lysosomal protein degradation homeostasis.
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spelling pubmed-72621602020-06-09 “LRRK2: Autophagy and Lysosomal Activity” Madureira, Marta Connor-Robson, Natalie Wade-Martins, Richard Front Neurosci Neuroscience It has been 15 years since the Leucine-rich repeat kinase 2 (LRRK2) gene was identified as the most common genetic cause for Parkinson’s disease (PD). The two most common mutations are the LRRK2-G2019S, located in the kinase domain, and the LRRK2-R1441C, located in the ROC-COR domain. While the LRRK2-G2019S mutation is associated with increased kinase activity, the LRRK2-R1441C exhibits a decreased GTPase activity and altered kinase activity. Multiple lines of evidence have linked the LRRK2 protein with a role in the autophagy pathway and with lysosomal activity in neurons. Neurons rely heavily on autophagy to recycle proteins and process cellular waste due to their post-mitotic state. Additionally, lysosomal activity decreases with age which can potentiate the accumulation of α-synuclein, the pathological hallmark of PD, and subsequently lead to the build-up of Lewy bodies (LBs) observed in this disorder. This review provides an up to date summary of the LRRK2 field to understand its physiological role in the autophagy pathway in neurons and related cells. Careful assessment of how LRRK2 participates in the regulation of phagophore and autophagosome formation, autophagosome and lysosome fusion, lysosomal maturation, maintenance of lysosomal pH and calcium levels, and lysosomal protein degradation are addressed. The autophagy pathway is a complex cellular process and due to the variety of LRRK2 models studied in the field, associated phenotypes have been reported to be seemingly conflicting. This review provides an in-depth discussion of different models to assess the normal and disease-associated role of the LRRK2 protein on autophagic function. Given the importance of the autophagy pathway in Parkinson’s pathogenesis it is particularly relevant to focus on the role of LRRK2 to discover novel therapeutic approaches that restore lysosomal protein degradation homeostasis. Frontiers Media S.A. 2020-05-25 /pmc/articles/PMC7262160/ /pubmed/32523507 http://dx.doi.org/10.3389/fnins.2020.00498 Text en Copyright © 2020 Madureira, Connor-Robson and Wade-Martins. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Madureira, Marta
Connor-Robson, Natalie
Wade-Martins, Richard
“LRRK2: Autophagy and Lysosomal Activity”
title “LRRK2: Autophagy and Lysosomal Activity”
title_full “LRRK2: Autophagy and Lysosomal Activity”
title_fullStr “LRRK2: Autophagy and Lysosomal Activity”
title_full_unstemmed “LRRK2: Autophagy and Lysosomal Activity”
title_short “LRRK2: Autophagy and Lysosomal Activity”
title_sort “lrrk2: autophagy and lysosomal activity”
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262160/
https://www.ncbi.nlm.nih.gov/pubmed/32523507
http://dx.doi.org/10.3389/fnins.2020.00498
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