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

Abstract

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.

• Authors: Yongle Li, Jun Zhang, Chunxiang Yang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 459 Issue 2 Pg. 196-200 (Apr 03 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25680463 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• RNA, Messenger
• Recombinant Proteins
• Autophagy-Related Protein-1 Homolog
• Protein Serine-Threonine Kinases
• Ribosomal Protein S6 Kinases, 90-kDa
• Rps6ka1 protein, mouse
• Ulk1 protein, mouse
• 1-Methyl-4-phenylpyridinium

Topics

• 1-Methyl-4-phenylpyridinium (toxicity)
• Amino Acid Substitution
• Animals
• Autophagy-Related Protein-1 Homolog
• Binding Sites (genetics)
• Cell Line
• Cell Survival
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, metabolism, pathology)
• Gene Knockdown Techniques
• Mice
• Mutagenesis, Site-Directed
• Nerve Degeneration (etiology, metabolism, pathology)
• Parkinsonian Disorders (etiology, metabolism, pathology)
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Recombinant Proteins (chemistry, genetics, metabolism)
• Ribosomal Protein S6 Kinases, 90-kDa (chemistry, genetics, metabolism)