The role of the E3 ligase RNF157 in neuronal survival

神经细胞死亡是神经退行性疾病的标志。然而，我们对潜在机制的理解非常有限。泛素蛋白酶体系统已成为各种神经发育事件的关键调节剂，包括神经发生、迁移、轴突和树突生长以及突触形成。然而，关于UPS在神经退行性变中的作用知之甚少。在组成UPS的成分中，E3泛素连接酶数量最多。Mahogunin-1是为数不多的E3连接酶之一，与神经变性有关。该提案的目标是描述mahogunin -1相关E3连接酶RNF157在神经元存活中的机制。我们的初步数据表明，大脑特异性蛋白RNF157在神经元中具有促进存活的作用。此外，我们发现支架蛋白FE65是RNF157的相互作用因子，并发现FE65功能获得诱导细胞凋亡。此外，我们已经建立了RNF157基因敲除小鼠，这是胚胎致死的。拟开展的研究目的如下：第一个目的是对RNF157基因敲除小鼠进行组织学和行为学分析。在这里，我们将在组织学水平上分析纯合子和杂合子小鼠，并通过行为测试检测杂合子RNF157动物。第二个目标，我们将描述神经元存活的RNF157通路。该实验将使用功能损失和增益分析以及结构-功能分析来检查RNF157-FE65在神经元存活中的相互作用。综上所述，本研究将研究新的E3连接酶RNF157在神经元存活中的作用，从而揭示支持神经元健康的新途径，并最终更好地理解神经退行性过程。

Neuronal cell death is a hallmark of neurodegenerative diseases. However, our understanding of the underlying mechanisms is very limited. The ubiquitin proteasome system has emerged as a crucial regulator of various neurodevelopmental events including neurogenesis, migration, axon and dendrite growth, and synapse formation. However, little is known about the role of the UPS in neurodegeneration. Among the components that comprise the UPS, E3 ubiquitin ligases are the most numerous. Mahogunin-1 is one of the few E3 ligases, which have been implicated in neurodegeneration. The goal of the proposal is to delineate the mechanism underlying the Mahogunin-1-related E3 ligase RNF157 in neuronal survival. Our preliminary data indicate a prosurvival role of the brain-specific protein RNF157 in neurons. Also, we identified the scaffold protein FE65 as an interactor of RNF157 and found that FE65 gain-of-function induces apoptosis. In addition, we have established an RNF157 knockout mouse, that is embryonic lethal. The aims of the proposed research are as follows: The first aim will be the histological and behavioral analyses of RNF157 knockout mice. Here, we will analyze both homozygous and heterozygous mice at the histological level and examine heterozygous RNF157 animals with behavioral tests. With the second aim, we will delineate the RNF157 pathway of neuronal survival. The proposed experiments will examine the RNF157-FE65 interaction in neuronal survival using loss- and gain-of function analyses together with structure-function analyses. Taken together, this proposal will examine the novel E3 ligase RNF157 in neuronal survival to shed light onto novel pathways that support neuronal health and ultimately allow a better understanding of neurodegenerative processes.