Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University; Fuzhou, China.
Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University; Fuzhou, China.
Neurochem Int. 2023 Oct;169:105589. doi: 10.1016/j.neuint.2023.105589. Epub 2023 Aug 4.
As a ubiquitous RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) interacts with numerous nucleic acids and proteins and is involved in various cellular functions. Available literature indicates that it can regulate dendritic spine density through the extracellular signal-regulating kinase (ERK) - brain-derived neurotrophic factor (BDNF) pathway, which is crucial to retain the synaptic plasticity in patients with major depressive disorder (MDD) and mouse depression models. However, ERK upstream regulatory kinase has not been fully elucidated. Furthermore, it remains unexplored whether hnRNPK may impact the depressive condition via the ERK pathway. The present study addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing. We found that hnRNPK in the brain was mainly distributed in the hippocampal neurons; that it was significantly downregulated in mice that displayed stress-induced depression-like behaviors; and that the level of hnRNPK markedly decreased in MDD patients from the GEO database. Further in vivo and in vitro analyses revealed that the changes in the expressions of BDNF and PSD95 and in the phosphorylation of ERK (Thr202/Tyr204) paralleled the variation of hnRNPK levels in the ventral hippocampal neurons in mice with depression-like behaviors. Finally, esketamine treatment significantly increased the level of hnRNPK in mice. These findings evidence that hnRNPK involved in the pathogenesis of depression via the ERK-BDNF pathway, pinpointing hnRNPK as a potential therapeutic target in treating MDD patients.
作为一种普遍存在的 RNA 结合蛋白，异质核核糖核蛋白 K（hnRNPK）与许多核酸和蛋白质相互作用，并参与各种细胞功能。现有文献表明，它可以通过细胞外信号调节激酶（ERK）-脑源性神经营养因子（BDNF）通路调节树突棘密度，这对于维持重度抑郁症（MDD）患者和小鼠抑郁模型中的突触可塑性至关重要。然而，ERK 的上游调节激酶尚未完全阐明。此外，hnRNPK 是否可以通过 ERK 通路影响抑郁状态仍不清楚。本研究通过整合遗传学、分子生物学和行为测试方法来解决这个问题。我们发现大脑中的 hnRNPK 主要分布在海马神经元中；在表现出应激诱导的抑郁样行为的小鼠中，hnRNPK 显著下调；并且 GEO 数据库中的 MDD 患者的 hnRNPK 水平明显降低。进一步的体内和体外分析表明，BDNF 和 PSD95 的表达变化以及 ERK（Thr202/Tyr204）的磷酸化与抑郁样行为小鼠腹侧海马神经元中 hnRNPK 水平的变化平行。最后，氯胺酮治疗显著增加了小鼠中 hnRNPK 的水平。这些发现证明 hnRNPK 通过 ERK-BDNF 通路参与抑郁症的发病机制，指出 hnRNPK 作为治疗 MDD 患者的潜在治疗靶点。
