Kyushu University Academic Staff Educational and Research Activities Database
List of Presentations
Daisuke Tsuchimoto Last modified date:2021.11.02

Assistant Professor / Division of Neurofunctional Genomics / Department of Immunobiology and Neuroscience / Medical Institute of Bioregulation

1. 土本大介、古賀祐一郎、林良憲、アボルハッサニ ノナ、米嶋康臣、作見邦彦、中西博、豊國伸哉、中別府雄作, Neural stem cell-specific Itpa knockout causes depolarization, epileptic seizure and early death in mice, 第43回日本神経科学大会, 2020.09.
2. Daisuke Tsuchimoto, Yuichiro Koga, Yoshinori Hayashi, Nona Abolhassani,Yasuto Yoneshima, Hiroshi Nakanishi, Yusaku Nakabeppu, Neural stem cell-specific Itpa knockout mouse as a model of human epileptic encephalopathy caused by ITPA deficiency, The Joint Symposium of the 13th International Symposium of the Institute Network for Biomedical Sciences and the 28th Hot Spring Harbor International Symposium 2018, 2018.10.
3. Daisuke Tsuchimoto, Yuichiro Koga, Yoshinori Hayashi, Nona Abolhassani, Yasuto Yoneshima, Hiroshi Nakanishi, Yusaku Nakabeppu, Neural stem cell-specific Itpa knockout mouse as a model of human ITPA deficiency, 第41回日本神経科学大会, 2018.07, Inosine triphosphate pyrophosphatase (ITPA), which is encoded by ITPA gene, hydrolyzes ITP and other deaminated purine nucleoside triphosphates to the corresponding nucleoside monophosphates and pyrophosphates, thus sanitizing intracellular nucleotide pools. In human, it was recently reported that patients with ITPA homozygous mutations show severe encephalopathy with epileptic seizure and microcephaly. All patients show developmental retardation and most of them die before 3 years old.
We previously reported that ITPA deficiency in mice causes partial embryonic lethality and survived litters also die within 2 weeks after birth with features of growth retardation. Echocardiography and ultrastructural analysis of hearts of Itpa knockout mice revealed unsynchronized movement and disorganized sarcomere structure.
In the present study, we established and analyzed neural stem cell-specific Itpa knockout mice (Itpaflox/flox/Nestin-Cre+/Tg). Knockout in the neural stem cells results in ITPA deficiency in neurons and glial cells except microglia. Itpaflox/flox/Nestin-Cre+/Tg mice did not exhibit embryonic lethality, but showed growth retardation and died within 3 weeks after birth. Some of them showed spontaneous and generalized seizure. Artificial audiogenic stress induced similar seizure in all analyzed knockout mice but not in ITPA-proficient control mice. In contrast to human patients, the ITPA deficient mice did not show microcephaly.
To analyze molecular mechanism of the seizure caused by ITPA deficiency in brain, we performed electrophysiological analysis of brain slices. Whole-cell patch-clamp recordings from entorhinal cortex neurons in Itpaflox/flox/Nestin-Cre+/Tg brain slices showed depolarized resting membrane potential and more frequent firing rates both under spontaneous and stimulated conditions, in comparison to those in wild-type brain slices. The membrane potential in neuron is generated by ion channels and sodium/potassium-transporting ATPase (Na+/K+-ATPase), which contains ATP1A1 or ATP1A3 as its  subunit ATPase. Biochemical analysis of recombinant ATP1A1 or ATP1A3 showed that ITP is not good substrate for them and does not inhibit their ATPase activities, suggesting that ITPA deficiency may cause depolarization of resting membrane potential via other mechanisms such as alteration of ion channel function..
4. Mechanism of genome instability triggered by deoxyinosine nucleotides and defense systems in mammalian cells.
5. Genome instability triggered by deoxyinosine nucleotides and defense mechanisms in mammalian cells.
6. Nona Abolhassani, Teruaki Iyama, Daisuke Tsuchimoto, SAKUMI Kunihiko, Ohno Mizuki, Mehrdad Behmanesh, Yusaku Nakabeppu, NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals., The 7th 3R Symposium, 2010.10.
7. Teruaki Iyama, Nona Abolhassani, Daisuke Tsuchimoto, Mari Nonaka, Yusaku Nakabeppu, NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest., The 7th 3R Symposium, 2010.10.
8. Daisuke Tsuchimoto, Teruaki Iyama, Nona Abolhassani, Yusaku Nakabeppu, Human NUDT16 is a novel nucleotide pool sanitizing enzyme hydrolyzing (deoxy)inosine diphosphate to (deoxy)inosine monophosphate, 第32回日本分子生物学会年会, 2009.12.
9. Screening of damaged nucleotide binding proteins by using ATP immobilized resin.
10. Biochemical charateristics of ITP binding protein, ITPBP1.
11. Decrease of peripheral white blood cells in Neil3 KO mice.
12. Retardation of production of anti-ovalubmin antibody in APEX2-null mice.