うつ病・自殺と関連する脳内物質の発見(Brain Chemical Linked to Suicide Risk after Childhood Trauma)

2025-10-20

2025-10-15 コロンビア大学

コロンビア大学医学部とマギル大学の共同研究により、幼少期にトラウマを経験した人は、脳内の酵素SGK1(血清・糖質コルチコイド調節キナーゼ1)の過剰発現により、うつ病や自殺リスクが高まることが明らかになった。研究では、自殺者の脳組織や未治療のうつ病患者の血液を解析し、幼少期逆境歴のある群でSGK1が著しく高いことを確認。また、遺伝的にSGK1発現を増やす変異を持つ人は、思春期にうつ病を発症しやすい傾向が見られた。さらに、マウス実験でSGK1阻害剤を投与するとストレス誘発性の抑うつ行動を防げることが示され、SGK1は新たな抗うつ治療標的となる可能性がある。幼少期トラウマが脳の分子機構に長期的影響を与えることを示す重要な成果である。

<関連情報>

海馬SGK1はうつ病への脆弱性を促進する:幼少期の逆境、ストレス、遺伝的リスクの役割Hippocampal SGK1 promotes vulnerability to depression: the role of early life adversity, stress, and genetic risk

Amira Millette,Milenna T. van Dijk,Irina Pokhvisneva,Yifei Li,Rory Thompson,Sachin Patel,Rosemary C. Bagot,Aniko Naray-Fejes-Toth,Geza Fejes-Toth,Patricia Pelufo Silveira,Gustavo Turecki,Juan Pablo Lopez & Christoph Anacker
Molecular Psychiatry Published:01 October 2025
DOI:https://doi.org/10.1038/s41380-025-03269-6

Abstract

Serum and Glucocorticoid-regulated Kinase 1 (SGK1) is elevated in hippocampal neurons following glucocorticoid exposure and in peripheral blood of depressed patients. However, its mechanistic role in psychopathology and its relevance to the human brain are unknown. To address this gap, we investigated human postmortem brain tissue and found higher SGK1 expression in the hippocampus of depressed suicide decedents compared to healthy subjects who died of natural causes. We observed the highest levels of SGK1 in subjects with reported early life adversity (ELA) – a major risk factor for psychiatric disorders. To determine potential genetic factors underlying increased SGK1 in the hippocampus, we computed expression-based polygenic risk scores (ePRS) for a large population sample from the ABCD study and found that a collection of genetic variants associated with high hippocampal SGK1 expression predicts depression severity and moderates associations between ELA, depressive symptoms, and suicide attempts. Similar to the human brain, hippocampal SGK1 expression was increased in mouse models of ELA, adult chronic stress, and chronic corticosterone exposure, and hippocampal-specific knockdown of SGK1 conferred resilience to stress-induced behavior abnormalities. To test SGK1 as a potential therapeutic target, we injected mice with the small molecule inhibitor, GSK650394, and found that pharmacological inhibition conferred stress resilience, increased adult hippocampal neurogenesis, and rescued stress-induced dentate gyrus hyperactivity. Our cross-species findings reveal a novel role for hippocampal SGK1 in stress resilience, highlight an interaction between ELA and SGK1 on depression and suicide risk, and establish for the first time a functional role for SGK1 in stress-induced psychopathology.