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

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1864; no. 12; pp. 2356 - 2368
• Main Authors: Yoon, Ji-Hye, Mo, Jung-Soon, Kim, Mi-Yeon, Ann, Eun-Jung, Ahn, Ji-Seon, Jo, Eun-Hye, Lee, Hye-Jin, Lee, Young Chul, Seol, Wongi, Yarmoluk, Sergiy M., Gasser, Thomas, Kahle, Philipp J., Liu, Guang-Hui, Belmonte, Juan Carlos Izpisua, Park, Hee-Sae
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2017
• Subjects: Apoptosis - genetics; ASK1; Humans; Induced Pluripotent Stem Cells - metabolism; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; LRRK2; MAP Kinase Kinase 3 - genetics; MAP Kinase Kinase 3 - metabolism; MAP Kinase Kinase Kinase 5 - genetics; MAP Kinase Kinase Kinase 5 - metabolism; MAPK; Neuronal cell death; Neurons - metabolism; Neurons - pathology; p38 Mitogen-Activated Protein Kinases - genetics; Parkinson Disease - genetics; Parkinson Disease - pathology; Phosphorylation; Signal Transduction - genetics; Phosphorylation; MAPK; LRRK2; ASK1; Neuronal cell death
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2017.09.001

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. •LRRK2 Acts as an Upstream Kinase and Regulates the ASK1 Pathway.•LRRK2 Physically Interacts with ASK1 Signaling Kinases and Acts as a Scaffolding Protein.•LRRK2 Interacts with ASK1 in a JIP1-Independent Manner.•LRRK2 Promotes Neuronal Cell Death by Phosphorylating ASK1 at Thr832.•LRRK2 Induces Apoptosis of Patient-Derived NSCs in an ASK1-Dependent Manner.