Brito David V C, Kupke Janina, Gulmez Karaca Kubra, Oliveira Ana M M
Institute of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, INF 366, 69120, Heidelberg, Germany.
Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, 8005-139, Faro, Portugal.
Curr Res Neurobiol. 2022 Feb 15;3:100031. doi: 10.1016/j.crneur.2022.100031. eCollection 2022.
Neurons respond rapidly to extracellular stimuli by activating signaling pathways that modulate the function of already synthetized proteins. Alternatively, signal transduction to the cell nucleus induces synthesis of proteins required for long-lasting adaptations. These complementary strategies are necessary for neuronal plasticity processes that underlie, among other functions, the formation of memories. Nonetheless, it is still not fully understood how the coupling between different stimuli and the activity of constitutively and/or expressed proteins gate neuronal plasticity. Here, we discuss the molecular functions of the Growth Arrest and DNA Damage 45 (Gadd45) family of proteins in neuronal adaptation. We highlight recent findings that indicate that Gadd45 family members regulate this function through multiple cellular processes (e.g., DNA demethylation, gene expression, RNA stability, MAPK signaling). We then summarize the regulation of Gadd45 expression in neurons and put forward the hypothesis that the constitutive and neuronal activity-induced pools of Gadd45 proteins have distinct and complementary roles in modulating neuronal plasticity. Therefore, we propose that Gadd45 proteins are essential for brain function and their dysfunction might underlie pathophysiological conditions such as neuropsychiatric disorders.
神经元通过激活调节已合成蛋白质功能的信号通路，对细胞外刺激做出快速反应。另外，信号转导至细胞核会诱导合成持久适应性所需的蛋白质。这些互补策略对于神经元可塑性过程是必要的，而神经元可塑性过程是形成记忆等多种功能的基础。尽管如此，不同刺激与组成型和/或表达的蛋白质活性之间的耦合如何控制神经元可塑性，仍未完全清楚。在这里，我们讨论生长停滞和DNA损伤45（Gadd45）蛋白家族在神经元适应性中的分子功能。我们强调最近的发现，即Gadd45家族成员通过多种细胞过程（如DNA去甲基化、基因表达、RNA稳定性、MAPK信号传导）调节这一功能。然后，我们总结了神经元中Gadd45表达的调控，并提出假说：组成型和神经元活性诱导的Gadd45蛋白池在调节神经元可塑性方面具有不同且互补的作用。因此，我们认为Gadd45蛋白对脑功能至关重要，其功能障碍可能是神经精神疾病等病理生理状况的基础。
