Leucine-rich repeat kinase 2 induces α-synuclein expression via the extracellular signal-regulated kinase pathway
| Autor: | Giorgio Rovelli, Iria Carballo-Carbajal, Diane Chan, Benjamin Wolozin, Susanne Weber-Endress, Thomas Gasser, Christian Klein, Philipp J. Kahle, Nadja Patenge |
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| Rok vydání: | 2010 |
| Předmět: |
Time Factors
Transcription Genetic MAP Kinase Signaling System MAP Kinase Kinase 2 Protein Serine-Threonine Kinases Mitogen-activated protein kinase kinase Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Article Cell Line MAP2K7 Nitriles Butadienes Humans ASK1 RNA Messenger c-Raf Phosphorylation Extracellular Signal-Regulated MAP Kinases biology MAP kinase kinase kinase Cyclin-dependent kinase 4 Cyclin-dependent kinase 2 Parkinson Disease Cell Biology Molecular biology Up-Regulation nervous system diseases Enzyme Activation Protein Transport Mutation alpha-Synuclein biology.protein Mutant Proteins Cyclin-dependent kinase 9 |
| Zdroj: | Cellular Signalling. 22:821-827 |
| ISSN: | 0898-6568 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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