Analysis of AGE modification of CRMP2 by carbonyl stress

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07616
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Toyoshima Manabu 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (90582750)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 統合失調症 / CRMP2 / カルボニルストレス

Outline of Final Research Achievements

Impairments in neurodevelopmental process are thought to play a pivotal role in the pathogenesis of schizophrenia. To date, carbonyl stress have been identified as pathophysiological factors for schizophrenia, but it is unclear by molecular mechanism underlying carbonyl stress affects neural differentiation and development. Here, we elucidated the molecular mechanism underlying the effects of carbonyl stress in GLO I KO iPS cells. The GLO I KO iPS cells exhibited significant cellular and developmental deficits, and hyper-AGE modification of CRMP2. Structural and biochemical analyses revealed that AGE modificated CRMP2 was stacked in the multimer conformation by irreversible cross-linking, resulting in loss of function to bundle microtubules. Thus the current study revealed that the enhanced carbonyl stress stemmed from the genetic aberrations results in neurodevelopmental deficits through the formation of irreversible dysfunctional multimer of AGE modificated CRMP2.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

カルボニルストレスを伴う統合失調症において、AGE修飾を受けたCRMP2タンパク質が多量体化して細胞骨格の制御機能を失うことが疾患病態の基盤にある可能性を初めて示した。
これまでカルボニルストレスがどのように統合失調症の病態を引き起こすのか不明であったが、患者由来iPS細胞と原子レベルの構造解析によって新しい分子経路が明らかになった。カルボニルストレスを伴う統合失調症の詳細な分子病態が明らかになったことにより、統合失調症における分子標的治療・創薬、及び発症予防法開発を促進する基盤となる。