LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death

Biochim Biophys Acta Mol Cell Res. 2017 Dec;1864(12):2356-2368. doi: 10.1016/j.bbamcr.2017.09.001. Epub 2017 Sep 6.


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.

Keywords: ASK1; LRRK2; MAPK; Neuronal cell death; Phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • MAP Kinase Kinase 3 / genetics
  • MAP Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase Kinase 5 / genetics*
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Neurons / metabolism*
  • Neurons / pathology
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Phosphorylation
  • Signal Transduction / genetics
  • p38 Mitogen-Activated Protein Kinases / genetics


  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase 3