Document Detail


Leucine-rich repeat kinase 2 induces alpha-synuclein expression via the extracellular signal-regulated kinase pathway.
MedLine Citation:
PMID:  20074637     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of autosomal-dominant Parkinson's disease (PD). The second known autosomal-dominant PD gene (SNCA) encodes alpha-synuclein, which is deposited in Lewy bodies, the neuropathological hallmark of PD. LRRK2 contains a kinase domain with homology to mitogen-activated protein kinase kinase kinases (MAPKKKs) and its activity has been suggested to be a key factor in LRRK2-associated PD. Here we investigated the role of LRRK2 in signal transduction pathways to identify putative PD-relevant downstream targets. Over-expression of wild-type [wt]LRRK2 in human embryonic kidney HEK293 cells selectively activated the extracellular signal-regulated kinase (ERK) module. PD-associated mutants G2019S and R1441C, but not kinase-dead LRRK2, induced ERK phosphorylation to the same extent as [wt]LRRK2, indicating that this effect is kinase-dependent. However, ERK activation by mutant R1441C and G2019S was significantly slower than that for [wt]LRRK2, despite similar levels of expression. Furthermore, induction of the ERK module by LRRK2 was associated to a small but significant induction of SNCA, which was suppressed by treatment with the selective MAPK/ERK kinase inhibitor U0126. This pathway linking the two dominant PD genes LRRK2 and SNCA may offer an interesting target for drug therapy in both familial and sporadic disease.
Authors:
Iria Carballo-Carbajal; Susanne Weber-Endress; Giorgio Rovelli; Diane Chan; Benjamin Wolozin; Christian L Klein; Nadja Patenge; Thomas Gasser; Philipp J Kahle
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-01-13
Journal Detail:
Title:  Cellular signalling     Volume:  22     ISSN:  1873-3913     ISO Abbreviation:  Cell. Signal.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-02-22     Completed Date:  2010-05-05     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  8904683     Medline TA:  Cell Signal     Country:  England    
Other Details:
Languages:  eng     Pagination:  821-7     Citation Subset:  IM    
Copyright Information:
2010 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Butadienes / pharmacology
Cell Line
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / metabolism*
Humans
MAP Kinase Kinase 2 / metabolism
MAP Kinase Signaling System* / drug effects
Mutant Proteins / metabolism
Mutation / genetics
Nitriles / pharmacology
Parkinson Disease / enzymology,  pathology
Phosphorylation / drug effects
Protein Transport / drug effects
Protein-Serine-Threonine Kinases / metabolism*
RNA, Messenger / genetics,  metabolism
Time Factors
Transcription, Genetic / drug effects
Up-Regulation / drug effects
alpha-Synuclein / genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
F30 NS066658-01A1/NS/NINDS NIH HHS; R01 ES015567/ES/NIEHS NIH HHS; R01 NS060872/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Butadienes; 0/Mutant Proteins; 0/Nitriles; 0/RNA, Messenger; 0/U 0126; 0/alpha-Synuclein; EC 2.7.1.-/MAP2K2 protein, human; EC 2.7.11.1/LRRK2 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.12.2/MAP Kinase Kinase 2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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