1. Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity
- Author
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Jie Ming, Bo Tian, Pei Zhang, Yang Shu, Qingzhi Wang, and Fengjuan Jiao
- Subjects
0301 basic medicine ,1-Methyl-4-phenylpyridinium ,lcsh:Medicine ,Mitogen-activated protein kinase kinase ,Toxicology ,Pathology and Laboratory Medicine ,Biochemistry ,MAP2K7 ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,Serine ,ASK1 ,Post-Translational Modification ,Phosphorylation ,lcsh:Science ,Cells, Cultured ,Neurons ,Mice, Knockout ,Neuronal Death ,Multidisciplinary ,Movement Disorders ,biology ,Cell Death ,In Vitro Kinase Assay ,Neurodegenerative Diseases ,Parkinson Disease ,Precipitation Techniques ,Up-Regulation ,Bioassays and Physiological Analysis ,Neurology ,Cell Processes ,Cellular Types ,Research Article ,Protein Binding ,Immunoblotting ,Molecular Sequence Data ,Mutation, Missense ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,Research and Analysis Methods ,Transfection ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,03 medical and health sciences ,Immunoprecipitation ,Animals ,Humans ,Amino Acid Sequence ,Kinase activity ,Molecular Biology Techniques ,Molecular Biology ,Enzyme Assays ,MAP kinase kinase kinase ,Toxicity ,Herbicides ,Cyclin-dependent kinase 5 ,Cyclin-dependent kinase 2 ,lcsh:R ,Biology and Life Sciences ,Proteins ,Cyclin-Dependent Kinase 5 ,Cell Biology ,Molecular biology ,nervous system diseases ,030104 developmental biology ,HEK293 Cells ,nervous system ,biology.protein ,Cyclin-dependent kinase 9 ,lcsh:Q ,Biochemical Analysis ,030217 neurology & neurosurgery - Abstract
Background Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson’s disease (PD). Among the mutations, LRRK2 c.4883G>C (R1628P) variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown. Principle Findings Unlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn’t alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5). Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+) phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl-4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5-dependent manner. Conclusion Our data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death.
- Published
- 2016