Sex-differences in proteasome-dependent K48-polyubiquitin signaling in the amygdala are developmentally regulated in rats.
Sex-differences in proteasome-dependent K48-polyubiquitin signaling in the amygdala are developmentally regulated in rats.
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DOI：
10.1186/s13293-023-00566-z
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发表时间：
2023-11-10
影响因子：
7.9
通讯作者：
Jarome, Timothy J.
中科院分区：
文献类型：
--
作者：
Farrell, Kayla;Auerbach, Aubrey;Liu, Catherine;Martin, Kiley;Pareno, Myasia;Ray, W. Keith;Helm, Richard F.;Biase, Fernando;Jarome, Timothy J.
在基线(休息)和与记忆相关的过程中涉及的分子机制的几个大脑区域已经观察到性别差异。泛素蛋白酶体系统(UPS)是细胞内主要的蛋白质降解途径。在赖氨酸-48(K48)-多泛素化中观察到了性别差异，这是UPS典型的降解标志，在基线和杏仁核内恐惧记忆形成期间都是如此。在这里，我们调查了这些基线性别差异出现的时间、方式和原因，以及是否两性都需要K48-多泛素标记来形成杏仁核的记忆。我们使用分子、生化和蛋白质组学方法相结合的方法，检测青春期前后雄性和雌性大鼠杏仁核中一个主要泛素编码基因(Uba52)的全局和蛋白质特异性K48-多泛素化和DNA甲基化水平，以确定性别差异是否受到发育调节。然后，我们使用行为和遗传方法来测试杏仁核中K48泛素化对于恐惧记忆形成的必要性。我们观察到发育调节的Uba52甲基化和总K48-多泛素化的基线差异，性成熟水平特别是在雌性大鼠中改变。K48-特定蛋白的多泛素化在雄性和雌性大鼠的发育过程中都会发生变化，但性别差异与年龄无关。最后，我们发现，雌性大鼠杏仁核中K48-多泛素化的遗传抑制会损害恐惧记忆的形成，而雄性大鼠不会。这些结果表明，K48-多泛素化以性别特异性的方式在杏仁核中以不同的蛋白质为靶标，而不考虑年龄。然而，性成熟在雌性大鼠K48-多泛素化水平的发育调节中起着重要作用。与这些数据一致的是，杏仁核中的K48-多聚泛素信号选择性地需要在雌性大鼠身上形成恐惧记忆。总之，这些数据表明，杏仁核中基线K48-多泛素化的性别差异是受发育调节的，这可能对更好地理解与焦虑相关障碍(如创伤后应激障碍(PTSD))相关过程中涉及的分子机制的性别差异具有重要意义。网上版载有补充材料，可在10.1186/s13293-023-00566-z查阅。男性和女性的大脑在大小、发育和细胞过程方面存在差异。此外，男性和女性患某些与焦虑相关的疾病的可能性存在差异，例如创伤后应激障碍(PTSD)。我们之前观察到在静息和行为训练的动物中，通过蛋白质修饰物泛素的标记来控制蛋白质破坏的细胞机制中的性别差异。我们发现，成年雌性大鼠在学习过程中“泛素化”不同的蛋白质，在杏仁核休息时比雄性大鼠有更多的泛素，杏仁核是控制情绪调节的大脑区域。这项研究调查了静息泛素的性别差异是否会随着动物年龄的增长而变化，包括泛素化的蛋白质以及泛素的数量是如何控制的。我们还调查了雄性和雌性大鼠是否需要泛素来形成记忆。我们发现，男性和女性泛化不同的蛋白质，但衰老也有助于这种变化，这表明性成熟可能是控制女性泛素数量的重要因素。最后，我们发现只有雌性大鼠需要杏仁核中的泛素来形成恐惧记忆。这些结果对于理解泛素活性在不同发育阶段的作用以及在两性中形成基于恐惧的记忆都很重要。由于女性比男性更容易患上创伤后应激障碍，这些数据可以帮助理解不同的细胞过程如何在创伤后应激障碍的发展过程中共同作用，以创造更好的治疗选择。网上版载有补充材料，可在10.1186/s13293-023-00566-z查阅。K48-多泛素化是典型的蛋白质降解标志，在发育过程中，雄性和雌性大鼠杏仁核中的蛋白质以基线为差异靶点。在雌性大鼠中，主要泛素编码基因Uba52的DNA甲基化和总体K48-多泛素化水平是发育调节的。雌性大鼠，但不是雄性大鼠，在杏仁核需要K48-多泛素信号来形成恐惧记忆，这表明雄性大鼠可能在恐惧记忆形成过程中利用另一种联系来进行蛋白质降解过程。网上版载有补充材料，可在10.1186/s13293-023-00566-z查阅。
Sex differences have been observed in several brain regions for the molecular mechanisms involved in baseline (resting) and memory-related processes. The ubiquitin proteasome system (UPS) is a major protein degradation pathway in cells. Sex differences have been observed in lysine-48 (K48)-polyubiquitination, the canonical degradation mark of the UPS, both at baseline and during fear memory formation within the amygdala. Here, we investigated when, how, and why these baseline sex differences arise and whether both sexes require the K48-polyubiquitin mark for memory formation in the amygdala. We used a combination of molecular, biochemical and proteomic approaches to examine global and protein-specific K48-polyubiquitination and DNA methylation levels at a major ubiquitin coding gene (Uba52) at baseline in the amygdala of male and female rats before and after puberty to determine if sex differences were developmentally regulated. We then used behavioral and genetic approaches to test the necessity of K48-polyubiquitination in the amygdala for fear memory formation. We observed developmentally regulated baseline differences in Uba52 methylation and total K48-polyubiquitination, with sexual maturity altering levels specifically in female rats. K48-polyubiquitination at specific proteins changed across development in both male and female rats, but sex differences were present regardless of age. Lastly, we found that genetic inhibition of K48-polyubiquitination in the amygdala of female, but not male, rats impaired fear memory formation. These results suggest that K48-polyubiquitination differentially targets proteins in the amygdala in a sex-specific manner regardless of age. However, sexual maturity is important in the developmental regulation of K48-polyubiquitination levels in female rats. Consistent with these data, K48-polyubiquitin signaling in the amygdala is selectively required to form fear memories in female rats. Together, these data indicate that sex-differences in baseline K48-polyubiquitination within the amygdala are developmentally regulated, which could have important implications for better understanding sex-differences in molecular mechanisms involved in processes relevant to anxiety-related disorders such as post-traumatic stress disorder (PTSD). The online version contains supplementary material available at 10.1186/s13293-023-00566-z. Male and female brains have differences in size, development, and cellular processes. Further, males and females have differences in likelihood of developing certain anxiety-related disorders, such as post-traumatic stress disorder (PTSD). We previously observed sex differences in a cellular mechanism that controls the destruction of proteins via tagging by the protein modifier ubiquitin in resting and behaviorally trained animals. We found that adult female rats “ubiquitinated” different proteins during learning and had more ubiquitin than male rats at rest in the amygdala, the brain region that controls emotional regulation. This study investigated if the sex difference in ubiquitin at rest changed as animals age, including the proteins being ubiquitinated and how the amount of ubiquitin was controlled. We also investigated if male and female rats need ubiquitin for memory formation. We found that males and females ubiquitinate different proteins, but that aging also contributes to changes in this, suggesting that sexual maturity may be important for controlling the amount of ubiquitin in females. Lastly, we found that only female rats needed ubiquitin in the amygdala for forming a fear memory. These results are important for understanding the role of ubiquitin activity at different developmental stages and for forming fear-based memories in both sexes. Since females are more likely to develop PTSD than males, these data could help understand how different cellular processes work together in PTSD development to create better treatment options. The online version contains supplementary material available at 10.1186/s13293-023-00566-z. K48-polyubiquitination, the canonical protein degradation mark, differentially targets proteins at baseline in the amygdala of male and female rats across development. DNA methylation at Uba52, a major ubiquitin coding gene, and overall K48-polyubiquitination levels are developmentally regulated in female rats. Female, but not male, rats require K48-polyubiquitin signaling in the amygdala for fear memory formation, suggesting males may utilize another linkage for protein degradation processes during fear memory formation. The online version contains supplementary material available at 10.1186/s13293-023-00566-z.
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