| Leucine-rich repeat kinase 2 induces alpha-synuclein expression via the extracellular signal-regulated kinase pathway. | |
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MedLine Citation:
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PMID: 20074637 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-01-13 |
Journal Detail:
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Title: Cellular signalling Volume: 22 ISSN: 1873-3913 ISO Abbreviation: Cell. Signal. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-02-22 Completed Date: 2010-05-05 Revised Date: 2012-11-16 |
Medline Journal Info:
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Nlm Unique ID: 8904683 Medline TA: Cell Signal Country: England |
Other Details:
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Languages: eng Pagination: 821-7 Citation Subset: IM |
Copyright Information:
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2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, Germany. icarballo@ir.vhebron.net |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Butadienes
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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:
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F30 NS066658-01A1/NS/NINDS NIH HHS; R01 NS060872/NS/NINDS NIH HHS; R01 NS060872-04/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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