Symposium Sessions
Day 1, June 10（Wed.） 14:44-15:02 Room C (4F 413)
- 1C-S1-1444（2P-01）
Inactivation of DNA Repair Kinase ATM and Pathomechanisms in Parkinson's Disease Revealed by Post‑translational Modification Proteomics
(Yokohama City Univ.)
oShunsuke Hoshina, Eri Katsuno, Masato Yoshizaki, Daisuke Takakura, Tohru Sugawara, Nana Kawasaki
Parkinson’s disease (PD) is characterized by motor dysfunctions and neural death due to decreased dopamine. The elevation of reactive oxygen species (ROS) and DNA damage has been identified. However, the mechanisms have remained unclear.
The increased phosphorylation promoted protein aggregation, whereas O-N-acetylglucosamine (O-GlcNAc) suppresses aggregation; therefore, the variation of post-translational modifications (PTM) has gathered interest in molecular mechanisms. However, the quantification of PTM proteins has been challenging because of their trace abundance. The enrichment process is often performed, but it reduces the accuracy of quantitative measurements. Data-independent acquisition mass spectrometry can avoid enrichment using spectral libraries of PTM peptides.
PD model dopaminergic neurons (DAs) and wild-type (WT) DAs were developed. ROS and α-Synuclein aggregation were quantified. The spectral libraries of phosphorylation and O-GlcNAcylation were developed on Skyline. Kinase activities were analyzed using a Kinase Substrate Enrichment Analysis.
PD-DAs demonstrated increased ROS and aggregated α-Synuclein. Phospho-proteomics exhibited decreased activity of ATM kinase and decreased phosphorylation in DNA repair proteins. Decreased O-GlcNAcylation in HCF1 was also confirmed. ATM inhibition in WT-DAs led to similar PD pathologies, phospho-proteome, and O-GlcNAc proteome signature. Therefore, the association of ATM inactivation with PD pathologies was identified.