Universität Tübingen
Signal Transduction Pathways Modulated by the PD-causative Gene LRRK2
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of autosomal-dominant Parkinson’s disease (PD). Post-mortem studies in PD brains have shown that alpha-synuclein (SNCA) aggregation is a frequent neuropathological hallmark of LRRK2-associated PD, However, the pathogenic mechanisms linking LRRK2 and SNCA are largely unknown. The LRRK2 kinase domain shares homology to mitogen-activated protein kinase kinase kinases (MAPKKKs) and its kinase activity has been suggested to be a key factor for LRRK2 pathogenesis. The objective of our study was to investigate the role of LRRK2 in PD-relevant signal transduction pathways and to identify putative downstream targets. Our results show that over-expression of wild-type LRRK2 in human embryonic kidney HEK293 cells induced the phosphorylation of extracellular signal-regulated kinases (ERK1/2) up to 4-fold without affecting basal levels of total ERK. Mutants R1441C and G2019S, but not kinase dead (KD), induced ERK activation to the same extent as wild-type LRRK2, indicating that ERK activation is dependent on LRRK2 kinase activity. Nonetheless, the time course of R1441C and G2019S induction was slower than that for wild-type LRRK2, despite similar expression levels. Furthermore, activation of the ERK pathway by LRRK2 was associated with an increase of almost 2-fold in SNCA mRNA, together with a small but significant increase in SNCA protein. Interestingly, SNCA up-regulation could be suppressed by treatment with the inhibitor U0126, which specifically blocks MEK1/2 activation, indicating that SNCA is induced by LRRK2 through ERK1/2 MAPK activation. This pathway links the two dominant PD-associated genes LRRK2 and SNCA, and opens a novel venue that may be relevant to pursuit the pathophysiology in both familial and sporadic PD and to search potential therapeutic targets.
Author and committee
dc:creator, dc:contributor.*- Author
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- Carballo-Carbajal, Iria
Identifiers
dc:identifier.*- Identifier
- hdl:10900/44084