The genomic DNA and its precursor nucleotides are always in danger of oxidation by reactive oxygen species (ROS) which are produced during the oxygen respiration and other normal metabolisms. Various oxidized bases and nucleotides are formed in DNA or nucleotide pools by ROS, and such oxidative lesions in nucleic acids cause mutations or cell death if they are not repaired or eliminated. Mutations induce cancers, and cell death is related to various neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases.
By analyzing the cell fate to either proliferate, arrest cell growth or initiate programmed cell death under oxidative stress, we have unveiled the mechanisms protecting genomic integrity from damage caused by ROS. Recently, we have shown that Fosb-null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior and that Fosb-null mouse is the first animal model to provide a genetic and molecular basis for the comorbidity between depression and epilepsy with abnormal neurogenesis, all of which are caused by loss of a single gene, Fosb. We recedntly found that Fosb gene regulates expression of C5ar1 gene in microglia thus controlling neuroinflamation. Moreover, we showed galectin-1 is highly accumulated in axons of motor neurons in ALS model mice.
Moreover,we demonstrated that 8-oxoguanine (8-oxoG), a major oxidized base lesion causes spontaneous germline mutations and carcinogenesis in mammals, and unveiled protective roles of MTH1, OGG1 and MUTYH. We have reported that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2‘-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress. We also demonstrated that MTH1 attenuates oxidative DNA damage and delays photoreceptor cell death in inherited retinal degeneration by sanitizing nucleotide pool in the photoreceptor cells.
1. Altered Expression of Diabetes-Related Genes in Alzheimer's Disease Brains: The Hisayama Study. Hokama M, Oka S, Leon J, Ninomiya T, Honda H, Sasaki K, Iwaki T, Ohara T, Sasaki T, LaFerla FM, Kiyohara Y, Nakabeppu Y. Cereb Cortex 24:2476-2488. 2014.
3. Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia. Nomaru H, Sakumi K, Katogi A, Ohnishi YN, Kajitani K, Tsuchimoto D, Nestler EJ, Nakabeppu Y. Glia 62: 1284-1298, 2014.
4. fosB-Null Mice Display Impaired Adult Hippocampal Neurogenesis and Spontaneous Epilepsy with Depressive Behavior. Yutsudo N, Kamada T, Kajitani K, Nomaru H, Katogi A, Ohnishi YH, Ohnishi YN, Takase K, Sakumi K, Shigeto H, Nakabeppu Y. Neuropsychopharmacology 38:895-906, 2013.
5. 8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair. Sheng Z, Oka S, Tsuchimoto D, Abolhassani N, Nomaru H, Sakumi K, Yamada H, Nakabeppu Y. J Clin Invest 122, 4344-4361. 2012.
6. MutT homolog-1 attenuates oxidative DNA damage and delays photoreceptor cell death in inherited retinal degeneration. Murakami Y, Ikeda Y, Yoshida N, Notomi S, Hisatomi T, Oka S, De Luca G, Yonemitsu Y, Bignami M, Nakabeppu Y, Ishibashi T. Am J Pathol 181:1378-1386, 2012.
7. FosB is essential for the enhancement of stress tolerance and antagonizes locomotor sensitization by ΔFosB. Ohnishi YN, Ohnishi YH, Hokama M, Nomaru H, Yamazaki K, Tominaga Y, Sakumi K, Nestler EJ, Nakabeppu Y. Biol Psychiatry 70: 487-495, 2011.
8. NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest. Iyama T, Abolhassani N, Tsuchimoto D, Nonaka M, Nakabeppu Y. Nucleic Acids Res 38: 4834-43, 2010.
9. 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. Abolhassani N, Iyama T, Tsuchimoto D, Sakumi K, Ohno M, Behmanesh M, Nakabeppu Y. Nucleic Acids Res 38: 2891-903, 2010.
10. ITPase-deficient mice show growth retardation and die before weaning. Behmanesh M, Sakumi K, Abolhassani N, Toyokuni S, Oka S, Ohnishi YN, Tsuchimoto D, Nakabeppu Y. Cell Death Differ 16: 1315-4322, 2009.
12. Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death. Ichikawa J, Tsuchimoto D, Oka S, Ohno M, Furuichi M, Sakumi K, Nakabeppu Y. DNA Repair 7: 418-30, 2008.
13. A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome. Ohno M, Miura T, Furuichi M, Tominaga Y, Tsuchimoto D, Sakumi K, Nakabeppu Y. Genome Res 16: 567-75, 2006.
14. MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Yamaguchi H, Kajitani K, Dan Y, Furuichi M, Ohno M, Sakumi K, Kang D, Nakabeppu Y. Cell Death Differ 13: 551-63, 2006.
15. MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity. Kajitani K, Yamaguchi H, Dan Y, Furuichi M, Kang D, Nakabeppu Y. J Neurosci 26: 1688-1698, 2006.
16. Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease. Arai T, Fukae J, Hatano T, Kubo S, Ohtsubo T, Nakabeppu Y, Mori H, Mizuno Y, Hattori N. Acta Neuropathol 112: 139-45, 2006.
17. Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice. Ide Y, Tsuchimoto D, Tominaga Y, Nakashima M, Watanabe T, Sakumi K, Ohno M, Nakabeppu Y. Blood 104: 4097-4103, 2004.
18. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. Yoshimura D, Sakumi K, Ohno M, Sakai Y, Furuichi M, Iwai S, Nakabeppu Y. J Biol Chem 278: 37965-37973, 2003.
19. A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. Sakai Y, Furuichi M, Takahashi M, Mishima M, Iwai S, Shirakawa M, Nakabeppu Y. J Biol Chem 277:8579-8587, 2002.
20. Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis. Kikuchi H, Furuta A, Nishioka K, Suzuki SO, Nakabeppu Y, Iwaki T. Acta Neuropathol 103: 408-14, 2002.
21. Expression of 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain. Iida T, Furuta A, Nishioka K, Nakabeppu Y, Iwaki T. Acta Neuropathologica 103: 20-25, 2002.