精神医学65巻4号

2023年04月発行

特集 わが国の若手による統合失調症研究最前線

カルボニルストレスと統合失調症

著者： 新井誠¹ 石田裕昭¹ 鳥海和也¹

所属機関： ¹東京都医学総合研究所精神行動医学研究分野統合失調症プロジェクト

ページ範囲：P.425 - P.434

抄録
　統合失調症は思春期から青年期に好発し，長期にわたり再発を繰り返すこともまれではなく，発症によって社会生活機能が低下するがゆえに，当事者のウェルビーイングやウェルエイジング促進のためにはより有効な治療や予防法，早期からの介入支援のあり方が希求されている。社会的な不利益や当事者のニーズが満たされないといった課題を解決するためにも，1つの方策として新たな分子に着目した病因や病態基盤の解明を推進し，基礎と臨床の多面的アプローチから社会への還元が不可欠である。
　筆者らはこれまで，終末糖化産物（advanced glycation end products：AGEs）という分子に着目し，統合失調症の一部が「カルボニルストレス（AGEs蓄積）」の病態像を呈することを同定した。これを機に，その病態を模倣したモデル研究から分子基盤の一端を明らかにしつつある。本稿では，筆者らが推進してきた研究の成果を中心に紹介し，統合失調症の発症とその病態とのかかわり，今後の展望について私見を交えながら述べた。

参考文献

1）Rabbani N, Thornalley PJ：Protein glycation-biomarkers of metabolic dysfunction and early-stage decline in health in the era of precision medicine. Redox Biol 42：101920, 2021

2）Chaudhuri J, Bains Y, Guha S, et al：The Role of Advanced Glycation End Products in Aging and Metabolic Diseases：Bridging Association and Causality. Cell Metab 28：337-352, 2018

3）Bollong MJ, Lee G, Coukos JS, et al：A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling. Nature 562：600-604, 2018

4）Sanghvi VR, Leibold J, Mina M, et al：The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase. Cell 178：807-819, 2019

5）Dai Z, Ramesh V, Locasale JW：The evolving metabolic landscape of chromatin biology and epigenetics. Nat Rev Genet 21：737-753, 2020

6）Diehl KL, Muir TW：Chromatin as a key consumer in the metabolite economy. Nat Chem Biol 16：620-629, 2020

7）Di Sanzo S, Spengler K, Leheis A, et al：Mapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation. Nat Commun 12：6743, 2021

8）McEwen JM, Fraser S, Guir ALS, et al：Synergistic sequence contributions bias glycation outcomes. Nat Commun 12：3316, 2021

9）Ishida YI, Kayama T, Kibune Y, et al：Identification of an argpyrimidine-modified protein in human red blood cells from schizophrenic patients：A possible biomarker for diseases involving carbonyl stress. Biochem Biophys Res Commun 493：573-577, 2017

10）Koike S, Toriumi K, Kasahara S, et al：Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits. Antioxidants（Basel） 10：574, 2021

11）Itakura M, Yamaguchi K, Kitazawa R, et al：Histone functions as a cell-surface receptor for AGEs. Nat Commun 13：2974, 2020

12）Solmi M, Radua J, Olivola M, et al：Age at onset of mental disorders worldwide：large-scale meta-analysis of 192 epidemiological studies. Mol Psychiatry 27：281-295, 2020

13）Dragioti E, Radua J, Solmi M, et al：Global population attributable fraction of potentially modifiable risk factors for mental disorders：a meta-umbrella systematic review. Mol Psychiatry 27：3510-3519, 2022

14）Kondo S, Kumakura Y, Kanehara A, et al：Premature deaths among individuals with severe mental illness after discharge from long-term hospitalisation in Japan：a naturalistic observation during a 24-year period. BJPsych Open 3：193-195, 2017

15）Miyashita M, Yamasaki S, Ando S, et al：Fingertip advanced glycation end products and psychotic symptoms among adolescents. NPJ Schizophr 7：37, 2021

16）Arai M, Yuzawa H, Nohara I, et al：Enhanced carbonyl stress in a subpopulation of schizophrenia. Arch Gen Psychiatry 67：589-597, 2010

17）Arai M, Miyashita M, Kobori A, et al：Carbonyl stress and schizophrenia. Psychiatry Clin Neurosci 68：655-665, 2014

18）Arai M, Koike S, Oshima N, et al：Idiopathic carbonyl stress in a drug-naive case of at-risk mental state. Psychiatry Clin Neurosci 65：606-607, 2011

19）Miyashita M, Arai M, Kobori A, et al：Clinical features of schizophrenia with enhanced carbonyl stress. Schizophr Bull 40：1040-1046, 2014

20）Kane J, Honigfeld G, Singer J, et al：Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45：789-796, 1988

21）Green MF, Kern RS, Braff DL, et al：Neurocognitive deficits and functional outcome in schizophrenia：are we measuring the “right stuff”? Schizophr Bull 26：119-136, 2000

22）Wykes T, Huddy V, Cellard C, et al：A meta-analysis of cognitive remediation for schizophrenia：methodology and effect sizes. Am J Psychiatry 168：472-485, 2011

23）Kobori A, Miyashita M, Miyano Y, et al：Advanced glycation end products and cognitive impairment in schizophrenia. PLoS One 16：e0251283, 2021

24）Carvalho AF, Solmi M, Sanches M, et al：Evidence-based umbrella review of 162 peripheral biomarkers for major mental disorders. Transl Psychiatry 10：152, 2020

25）Toriumi K, Miyashita M, Suzuki K, et al：Vitamin B6 deficiency hyperactivates the noradrenergic system, leading to social deficits and cognitive impairment. Transl Psychiatry 11：262, 2021

26）Ishida H, Miyashita M, Oshima K, et al：Carbonyl stress-sensitive brain regions in the patient with treatment-resistant schizophrenia with a glyoxalase 1 frameshift mutation：Autopsy study. Psychiatry Res Case Reports 1：100064, 2022

27）Valente T, Gella A, Fernàndez-Busquets X, et al：Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus. Neurobiol Dis 37：67-76, 2010

28）Dominguez MD, Wichers M, Lieb R, et al：Evidence that onset of clinical psychosis is an outcome of progressively more persistent subclinical psychotic experiences：an 8-year cohort study. Schizophr Bull 37：84-93, 2011

29）Suzuki K, Yamasaki S, Miyashita M, et al：Role of advanced glycation end products in the longitudinal association between muscular strength and psychotic symptoms among adolescents. Schizophrenia（Heidelb） 8：44, 2022