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    
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.
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
Butadienes / pharmacology
Cell Line
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / metabolism*
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
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 protein, human; EC Kinases; EC Signal-Regulated MAP Kinases; EC Kinase Kinase 2

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