Page 16 - ebook
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[B. Cell Biology/Stem Cell] B-8
LRRK2 controls the p38 MAPK pathway through activating
ASK1 in Parkinson's disease
Eun-Hye Jo¹, Mi-Yeon Kim¹, So-I Noh¹, Hyung-Ju Lee¹, Hee-Sae Park¹*
¹School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea
Leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein, is a key causative factor in Parkinson's disease (PD).
Identification of novel substrates and the molecular mechanisms underlying the effects of LRRK2 are essential for
understanding the pathogenesis of PD. In this study, we showed that LRRK2 played an important role in neuronal
cell death by directly phosphorylating and activating apoptosis signal-regulating kinase 1 (ASK1). LRRK2
phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site. Moreover,
results of binding and kinase assays showed that LRRK2 acted as a scaffolding protein by interacting with each
components of the ASK1–MKK3/6–p38 MAPK pathway through its specific domains and increasing the proximity to
downstream targets. Furthermore, LRRK2-induced apoptosis was suppressed by ASK1 inhibition in neuronal stem
cells derived from patients with PD. These results clearly indicate that LRRK2 acts as an upstream kinase in the ASK1
pathway and plays an important role in the pathogenesis of PD.
