Toward overcoming neurodegenerative disease by the circadian molecular clock study: — My 30 year history in a national institute —@@@— 国立研究所30年の総括 —

Abstract

The mammalian clock gene, Period2 , was discovered by my research group studying clock genes in 1998. I summarize the progress of understanding the circadian clock molecular mechanism after this discovery. Our group has demonstrated the importance of glycogen synthase kinase 3 – dependent phosphorylation of Period2 and its nuclear transfer and E4BP4 (vrille) negative transcriptional regulation, as well as Clock/Bmal, Period/Cry E-box dependent negative feedback loop. A role of myo-inositol for elongation of the circadian clock was uncovered through collaboration on iceplant projects with Tsujiko Co., Ltd, Shiga prefecture. When we started the molecular study of the circadian clock, we only considered the daily rhythm. Fortuitously, our research on the peripheral clock mechanism (PPARα) revealed a new mechanism of seasonal clocks, which can count photoperiods to adapt to winter (torpor). Our generation of researchers entered Japanese national institutes during a period called “the basic research shift era.” But, basic research grants were cut significantly during the 24 to 25 year period after we joined the institutes, and our research mission was abruptly changed to applied science. After several years of frustration and contemplation, we gave up studies using mice and concentrated on using Drosophila to reduce costs and save time. Consequently, we found a causative role of sleep abnormality around a young age in two neurodegenerative (Gaucher’s and Parkinson’s) diseases by using fly models. I summarize an application for the molecular mechanism of neurodegenerative disease. I am greatly thankful that I was able to spend more than 30 years on the study of molecular circadian clocks with the people who have been involved, from when I started as a researcher in 1986 at the Fermentation Research Institute of the Agency of Industrial Science and Technology to the present day at AIST. sleep, Neurodegenerative disease, Gaucher’s disease, Parkinson’s disease