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

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

Author information

1
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
2
Genomic Instability Research Center (GIRC), Ajou University School of Medicine, Suwon 16499, Republic of Korea.
3
InAm Neuroscience Research Center, Wonkwang University, Sanbon Hospital, Gunpo, Republic of Korea.
4
Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo Str., 03143 Kyiv, Ukraine.
5
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.
6
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
7
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
8
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea. Electronic address: proteome@jnu.ac.kr.

Abstract

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

PMID:
28888991
DOI:
10.1016/j.bbamcr.2017.09.001
[Indexed for MEDLINE]
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