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LRRK2 G2019S Mutation Inhibits Degradation of α-Synuclein in an In Vitro Model of Parkinson’s Disease

The G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of Parkinson’s disease (PD). However, the molecular mechanisms of LRRK2 mutation contributing to the onset and progression of PD have not been fully illustrated. We generated HEK293 cells stably transfec... Full description

Journal Title: Current Medical Science 2018, Vol.38(6), pp.1012-1017
Main Author: Hu, Dan
Other Authors: Niu, Jian-yi , Xiong, Jing , Nie, Shu-ke , Zeng, Fei , Zhang, Zhao-hui
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 2096-5230 ; E-ISSN: 2523-899X ; DOI: 10.1007/s11596-018-1977-z
Link: http://dx.doi.org/10.1007/s11596-018-1977-z
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recordid: springer_jour10.1007/s11596-018-1977-z
title: LRRK2 G2019S Mutation Inhibits Degradation of α-Synuclein in an In Vitro Model of Parkinson’s Disease
format: Article
creator:
  • Hu, Dan
  • Niu, Jian-yi
  • Xiong, Jing
  • Nie, Shu-ke
  • Zeng, Fei
  • Zhang, Zhao-hui
subjects:
  • α-synuclein
  • leucine-rich repeat kinase 2
  • Parkinson’s disease
  • lysosome
ispartof: Current Medical Science, 2018, Vol.38(6), pp.1012-1017
description: The G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of Parkinson’s disease (PD). However, the molecular mechanisms of LRRK2 mutation contributing to the onset and progression of PD have not been fully illustrated. We generated HEK293 cells stably transfected with α-synuclein and investigated the effect of LRRK2 G2019S mutation on the degradation of α-synuclein. The lysosomal activity was assessed by the protein degradation of glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A. It was found that α-synuclein was mainly degraded in lysosomes. LRRK2 G2019S inhibited the degradation of α-synuclein, and promoted its aggregation. LRRK2 G2019S also decreased the activities of lysosomal enzymes including cathepsin B and cathepsin L. Furthermore, the inhibitory effect of LRRK2 G2019S on lysosomal functions did not depend on its kinase activity. These findings indicated that the inhibitory effect of LRRK2 G2019S on α-synuclein degradation could underlie the pathogenesis of aberrant α-synuclein aggregation in PD with LRRK2 mutation.
language: eng
source:
identifier: ISSN: 2096-5230 ; E-ISSN: 2523-899X ; DOI: 10.1007/s11596-018-1977-z
fulltext: fulltext
issn:
  • 2523-899X
  • 2523899X
  • 2096-5230
  • 20965230
url: Link


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titleLRRK2 G2019S Mutation Inhibits Degradation of α-Synuclein in an In Vitro Model of Parkinson’s Disease
creatorHu, Dan ; Niu, Jian-yi ; Xiong, Jing ; Nie, Shu-ke ; Zeng, Fei ; Zhang, Zhao-hui
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subjectα-synuclein ; leucine-rich repeat kinase 2 ; Parkinson’s disease ; lysosome
descriptionThe G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of Parkinson’s disease (PD). However, the molecular mechanisms of LRRK2 mutation contributing to the onset and progression of PD have not been fully illustrated. We generated HEK293 cells stably transfected with α-synuclein and investigated the effect of LRRK2 G2019S mutation on the degradation of α-synuclein. The lysosomal activity was assessed by the protein degradation of glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A. It was found that α-synuclein was mainly degraded in lysosomes. LRRK2 G2019S inhibited the degradation of α-synuclein, and promoted its aggregation. LRRK2 G2019S also decreased the activities of lysosomal enzymes including cathepsin B and cathepsin L. Furthermore, the inhibitory effect of LRRK2 G2019S on lysosomal functions did not depend on its kinase activity. These findings indicated that the inhibitory effect of LRRK2 G2019S on α-synuclein degradation could underlie the pathogenesis of aberrant α-synuclein aggregation in PD with LRRK2 mutation.
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descriptionThe G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of Parkinson’s disease (PD). However, the molecular mechanisms of LRRK2 mutation contributing to the onset and progression of PD have not been fully illustrated. We generated HEK293 cells stably transfected with α-synuclein and investigated the effect of LRRK2 G2019S mutation on the degradation of α-synuclein. The lysosomal activity was assessed by the protein degradation of glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A. It was found that α-synuclein was mainly degraded in lysosomes. LRRK2 G2019S inhibited the degradation of α-synuclein, and promoted its aggregation. LRRK2 G2019S also decreased the activities of lysosomal enzymes including cathepsin B and cathepsin L. Furthermore, the inhibitory effect of LRRK2 G2019S on lysosomal functions did not depend on its kinase activity. These findings indicated that the inhibitory effect of LRRK2 G2019S on α-synuclein degradation could underlie the pathogenesis of aberrant α-synuclein aggregation in PD with LRRK2 mutation.
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titleLRRK2 G2019S Mutation Inhibits Degradation of α-Synuclein in an In Vitro Model of Parkinson’s Disease
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abstractThe G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of Parkinson’s disease (PD). However, the molecular mechanisms of LRRK2 mutation contributing to the onset and progression of PD have not been fully illustrated. We generated HEK293 cells stably transfected with α-synuclein and investigated the effect of LRRK2 G2019S mutation on the degradation of α-synuclein. The lysosomal activity was assessed by the protein degradation of glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A. It was found that α-synuclein was mainly degraded in lysosomes. LRRK2 G2019S inhibited the degradation of α-synuclein, and promoted its aggregation. LRRK2 G2019S also decreased the activities of lysosomal enzymes including cathepsin B and cathepsin L. Furthermore, the inhibitory effect of LRRK2 G2019S on lysosomal functions did not depend on its kinase activity. These findings indicated that the inhibitory effect of LRRK2 G2019S on α-synuclein degradation could underlie the pathogenesis of aberrant α-synuclein aggregation in PD with LRRK2 mutation.
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pubHuazhong University of Science and Technology
doi10.1007/s11596-018-1977-z
pages1012-1017
date2018-12