Analysis of the Pathogenesis of Novel Autoantibodies Targeting Synaptic Molecules in Psychiatric Disorders

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K08011
• 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: Tokyo Medical and Dental University
• Principal Investigator: Shiwaku Hiroki 東京医科歯科大学, 大学院医歯学総合研究科, テニュアトラック准教授 (90747502)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: 統合失調症 / 自己抗体 / NCAM1 / NRXN1 / シナプス / 自己免疫性精神病

Outline of Final Research Achievements

We identified that approximately 5.4% (12 out of 223) of patients with schizophrenia possess autoantibodies against NCAM1, a synaptic adhesion molecule not previously associated with encephalitis (Shiwaku et al., Cell Rep Med, 2022). Additionally, autoantibodies against NRXN1 were detected in 2.1% (8 out of 387) of patients (Shiwaku et al., Brain Behav Immun, 2023). Purified IgG from these autoantibody-positive patients was administered intrathecally into mice. This resulted in the inhibition of NCAM1-NCAM1 and NRXN1-NLGN1/2 intermolecular binding, leading to reduced synapse and spine density, and subsequently induced behaviors associated with schizophrenia.

Free Research Field

精神神経科学

Academic Significance and Societal Importance of the Research Achievements

現在の精神科領域の研究の中心課題は、難治性の病態の治療・バイオマーカーの確立・早期介入などである。本研究計画で明らかになった精神症状の原因となりえる自己抗体は、そのままバイオマーカーとなりえる。また、今後これらの自己抗体を除去する免疫学的治療の妥当性を治験等で明らかにできれば、難治性の病態の治療につながる。さらには、バイオマーカーとして、発症前からの早期介入にも寄与するなど、精神科領域の疾病概念や治療を大きく変える将来展望と波及効果がある。