Elucidating the functions of the E3 ubiquitin ligase FBXO7 - with a particular focus on myelinating cells

髓鞘胶质细胞为神经元中动作电位的快速传播提供了手段。这些细胞的完整性以及轴突-神经胶质相互作用的维持在很大程度上依赖于泛素蛋白酶体系统(UPS)所保证的它们的蛋白质稳态。E3泛素连接酶Fbxo7与青少年帕金森病和帕金森病相关性白质障碍多系统萎缩(MSA)有关。虽然我们的实验室已经确定Fbxo7在神经元中至关重要，但Fbxo7在髓鞘细胞中的作用仍有待确定。我们将在目标1中解决以下问题：Fbxo7的缺失如何影响中枢神经系统和三叉神经节髓鞘细胞的完整性？在目标2和目标3中，我们将分别研究Fbxo7在蛋白酶体和线粒体功能中的作用，因为我们的初步结果表明Fbxo7在这两个系统中的调节功能。因此，目标2如下：在蛋白酶体调节中，Fbxo7和蛋白酶体亚基PSMA2之间的生化关系的分子基础是什么？髓鞘细胞也是这样吗？目的3扩展了对Fbxo7功能的理解，并解决了以下问题：Fbxo7/MAP1B相互作用是否影响髓鞘细胞的微管动力学和/或线粒体的完整性？

Myelinating glial cells provide the means for the rapid propagation of action potentials in neurons. The integrity of these cells and thus the maintenance of the axon-glial interaction is critically dependent on the their protein homeostasis ensured by the ubiquitin proteasome system (UPS). The E3 ubiquitin ligase FBXO7 has been associated with juvenile parkinsonism and the parkinsonism-related white matter disorder multiple system atrophy (MSA). While we my lab has established that FBXO7 is critically important in neurons, the role of FBXO7 in myelinating cells remains to be characterized. We will address the following question in aim 1: How does the loss of FBXO7 affect the integrity of myelinating cells of the CNS and PNS? In aim 2 and 3, we will investigate the role of FBXO7 in proteasome and mitochondrial function, respectively, as our preliminary results point towards regulatory functions of FBXO7 in both systems. Hence, aim 2 is as follows: What are the molecular underpinnings of the biochemical relationship between FBXO7 and the proteasomal subunit PSMA2 in proteasome regulation? Is this true for myelination cells? Aim 3 expands the understanding of FBXO7 functions and addresses the following question: Does the FBXO7/MAP1B interaction affect microtubule dynamics and/or mitochondrial integrity in myelinating cells?