Bonomi Robin E, Naganawa Mika, McRiley Delaney, Toyonaga Takuya, LeVasseur Brittany, Duman Catharine, Huang Yiyun, Matuskey David, Carson Richard E, Pietrzak Robert H, Girgenti Matthew J, Cosgrove Kelly P
Yale University Department of Psychiatry, New Haven, CT, 06511, USA.
Yale PET Center, Yale University, New Haven, CT, 06511, USA.
Mol Psychiatry. 2025 Aug 2. doi: 10.1038/s41380-025-03124-8.
Histone deacetylases (HDACs), typically known for regulating gene expression, also play a major role in protein regulation outside of histone modification. Emerging evidence suggests the HDACs may be novel pharmacologic targets in complex disorders such as posttraumatic stress disorder (PTSD). Histone deacetylase 6 (HDAC6) regulates microtubule function and plays a role in stress-related cortisol signaling in serotonergic regions of the brain by maintaining the nuclear translocation of glucocorticoid receptors. Here, we report results of a translational positron emission tomography brain imaging study using a novel HDAC6-selective radiotracer, [F]Bavarostat. In humans, we demonstrate significantly lower availability of HDAC6 in the amygdala of individuals with PTSD compared to non-trauma exposed controls. These proof-of-concept human findings are supported by rodent findings of reduced HDAC6 availability both in case-control groups and within-subject longitudinal analysis using a single prolonged stress model. Together, our translational findings demonstrate a potential role for HDAC6 in the pathophysiology of PTSD.
组蛋白去乙酰化酶（HDACs）通常以调节基因表达而闻名，在组蛋白修饰之外的蛋白质调节中也发挥着重要作用。新出现的证据表明，HDACs可能是创伤后应激障碍（PTSD）等复杂疾病中的新型药理学靶点。组蛋白去乙酰化酶6（HDAC6）调节微管功能，并通过维持糖皮质激素受体的核转位，在大脑血清素能区域的应激相关皮质醇信号传导中发挥作用。在此，我们报告了一项使用新型HDAC6选择性放射性示踪剂[F]Bavarostat进行的正电子发射断层扫描脑成像转化研究的结果。在人类中，我们证明与未暴露于创伤的对照组相比，PTSD患者杏仁核中HDAC6的可用性显著降低。这些概念验证性的人类研究结果得到了啮齿动物研究结果的支持，即在病例对照组以及使用单一长期应激模型的受试者内部纵向分析中，HDAC6的可用性均降低。总之，我们的转化研究结果证明了HDAC6在PTSD病理生理学中的潜在作用。
