UNC-51-like kinase 1 blocks S6k1 phosphorylation contributes to neurodegeneration in Parkinson's disease model in vitro

作者：Li, Yongle^*; Zhang, Jun; Yang, Chunxiang

来源：Biochemical and Biophysical Research Communications, 2015, 459(2): 196-200.

DOI：10.1016/j.bbrc.2015.02.008

• Ribosomal protein s6 kinase 1
• UNC-51-like kinase 1
• Phosphorylation
• Parkinson's disease

Objective: This study was aim to determine the role and underling mechanism of ribosomal protein S6 kinases 1 (S6k1) phosphorylation in Parkinson's disease (PD). @@@ Methods: The dopaminergic neuron MN9D was employed and 1-methyl-4-phenylpyridium (MPP) iodide (MPP+) was used to generate PD model in vitro. The S6k1 phosphorylation and UNC-51-like kinase 1 (ULK1) protein levels were analyzed by western blot. The ULK1 mRNA level was evaluated by Real-time RT-PCR. The S6k1 threonine 389 (T389) site-directed mutagenesis, the phosphodeficit T389A (threonine to alanine) and the phosphomimetic T389D (threonine to aspartate) were generated to examine the phosphorylation site of S6k1. @@@ Results: An increase in the ULK1 mRNA and protein levels were detected in the MPP+-treated MN9D cells compared to control. ULK1 knockdown increased neuronal cell viability, and enhanced S6k1 phosphorylation. Further investigation demonstrated ULK1 knockdown promoted the S6k1 T389 phosphorylation in particular. T389A enhanced the viability of MPP iodide-treated MN9D, whereas T389D decreased the cell viability. @@@ Conclusion: ULK1 acts to inhibit S6k1 phosphorylation at T389, leading to MN9D viability reduction under MPP+ treatment. These results provide evidence for a novel mechanism by which the ULK1 inhibit S6k1 T389 phosphorylation contributes to neurodegeneration in MPP+ treated-MN9D, and suggests a new therapeutic strategy for PD.

• 出版日期2015-4-3
• 单位天津医科大学