|Budget Amount *help
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥6,500,000 (Direct Cost: ¥6,500,000)
Neuronal precursor cells proliferate during embryonic and early postnatal stage of mammalian development, however they lose their proliferative potential after differentiation into functional neurons. Neurons are expected to survive and function for the entire life of an individual, however, variotus damage accumulated during aging seems to cause their degeneration. Most energy required for neuronal function such as release of neurotransmitters is supplied by oxidative phosphorylation in mitochondria, where reactive oxygen species (ROS) are continuously produced. Thus, neurons are exposed to danger of oxidative damage by ROS, as a consequence of maintenance of their neuronal function.
In this project, based on the idea that oxidative damage of DNA and nucleotides are detrimental for maintaining functions of brain and neuronal cells, we have characterized the defense mechanisms against oxidative DNA damage in mammals including humanbeing, that is, sanitization of oxidized nucleotides and
repair of oxidaized bases in DNA.We have identified three enzymes involved in the processes, oxidized purine nucleoside triphosphatase encoded by MTH1 gene, 2-hydroxyadenine (2-OH-A)/adenine DNA glycosylase encoded by MYH gene, and 8-oxoguanine (8-oxoG) DNA glycosylase encoded by OGG1 gene, and analyzed their functions and regulatory mechanisms for their expression. We demonstrated that the three enzymes are involved in the maintenance of both nuclear and mitochondrial genomes, and further obtained data suggesting that alterations of their expression are involved in the process of neurogerenerative diseases in human.
Up to now, it has been accepted that DNA damage in brain or neuronal cells is not necessary to be repaired because they are postomitotic cells and their nuclear genomes are never replicated. However, our results strongly suggest that the maintenance and precise transcription of nuclear genonme is essential for the functions and survival of brain and neuronal cells, and further the maintenance of mitochondrial DNA is important in order to supply the energy essential for their function.
Since we have succeeded in establishing mutant mice for the three genes in this project, we are going to analyze the phenotypes of these mutant mice with combination of models for several neurodegenerative diseases. Our final goal is to establish biologcal roles of these defense mechanisms against oxidative DNA damage in brain and neuronal cells. Less