Neuronal membrane proteasome dependent regulation of PNS development and function

外周神经系统(PNS)的发育和功能需要蛋白质合成和蛋白质降解之间的平衡，这部分是由蛋白酶体复合体实现的。我们实验室发现了一种神经元特异性的跨膜型蛋白酶体复合体，它通过将多肽直接释放到中枢神经系统的细胞外间隙，在介导神经元信号转导中发挥新的作用。随着我们最近在三叉神经节中发现这种神经膜蛋白酶体(NMP)的存在，我们的目的是了解它在调节三叉神经节的发育和信号传递中的作用。我们的中心假设是，NMP介导的信号肽在三叉神经节神经元的发育和活动以及在介导轴突-神经胶质细胞的通讯中起着关键作用。我们这项工作的基本原理是，最近发现的NMP在三叉神经节中的功能尚不清楚，对其功能的了解将揭示新的神经元信号模式，这可能是三叉神经节最佳功能的关键。此外，虽然人们普遍认识到蛋白酶体信号在三叉神经节中对神经元发育和人类健康的影响，但影响三叉神经节的蛋白酶体调控通路的确切性质还没有被很好地描述。因此，我们的长期目标是了解NMP在PNS生物学中在健康和疾病中的作用。鉴于PNS中的NMP是最近在我们实验室发现的，因此出现了几个关键问题，这些问题构成了拟议实验的基础。具体为：Aim1.研究GPM6样蛋白在三叉神经节细胞膜蛋白酶体定位中的作用，验证我们的假说：在三叉神经节中，NMP通过与m6a/b糖蛋白结合而定位于神经细胞膜；目的2.研究PNS NMP在DRG神经元发育、髓鞘形成和活动中的作用，验证我们的假说：PNS NMP信号是正常髓鞘形成和全髓鞘PNS神经元功能所必需的。目的3.研究NMP多肽在轴突-神经胶质细胞通讯中的作用，验证我们的假设，即PNS轴突-神经胶质细胞通讯部分是通过NMP信号转导多肽实现的。这些目标的完成将为继续研究三叉神经节中神经细胞膜蛋白酶体信号转导奠定基础。

Development and function of the peripheral nervous system (PNS) requires a balance between protein synthesis and protein degradation, carried out in part by the proteasome complex. Our laboratory discovered a neuronal specific transmembrane-like proteasome complex with a new role in mediating neuronal signaling through direct peptide release into the extracellular space in the central nervous system. With our recent identification of the presence of this neuronal membrane proteasome (NMP) in the PNS our goal is to understand its role in mediating PNS development and signaling. Our central hypothesis is that NMP mediated signaling peptides have a pivotal role in PNS neuronal development and activity as well as in mediating axon-glia communication. Our rationale for this work is that the function of this recently identified NMP in the PNS is not understood and increasing the understanding of its function will reveal new modalities of neuronal signaling, which might be critical for optimal function of the PNS. Moreover, while a common appreciation for the impact of proteasomes signaling in the PNS in neuronal development and human health is understood the precise nature of the proteasome regulated pathways impacting PNS are not well delineated. Thus, our long-term goal is to understand the role of NMP in PNS biology in health and disease. Given the discovery of the NMP in the PNS was made recently in our laboratory several critical questions have emerged that make up the bases for the proposed experiments. Specifically: Aim1. To investigate the role of GPM6- like proteins in localizing membrane proteasomes in the PNS, to test our hypothesis that in the PNS NMP localizes to the neuronal membrane by associating with M6a/b glycoproteins; Aim 2. To investigate the requirement of PNS NMP in DRG neuron development, myelination, and activity, to test our hypothesis is that PNS NMP signaling is required for normal myelination and function of fully myelinated PNS neurons. Aim 3. To investigate the function of NMP peptides in axon-glia communication, to test our hypothesis that PNS axon-glia communication is, in part, mediated through NMP signaling peptides. The completion of the proposed aims will provide a foundation to continue the research that focuses on neuronal membrane proteasome signaling in the PNS.