Neuronal membrane proteasome dependent regulation of PNS development and function

周围神经系统（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，部分由蛋白酶体复合物进行。我们的实验室发现了一种神经元特异性的跨膜样蛋白酶体复合物，它在中枢神经系统中通过直接肽释放到细胞外空间介导神经元信号传导中起着新的作用。随着我们最近在PNS中发现这种神经元膜蛋白酶体（NMP）的存在，我们的目标是了解其在介导PNS发育和信号传导中的作用。我们的中心假设是NMP介导的信号肽在PNS神经元的发育和活动以及介导轴突-胶质细胞通讯中起关键作用。我们这项工作的基本原理是，最近发现的NMP在PNS中的功能尚不清楚，增加对其功能的理解将揭示神经元信号传导的新模式，这可能对PNS的最佳功能至关重要。此外，虽然对PNS中蛋白酶体信号传导在神经元发育和人类健康中的影响的普遍认识被理解，但影响PNS的蛋白酶体调节途径的确切性质尚未得到很好的描述。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。鉴于最近在我们的实验室中发现了PNS中的NMP，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:Aim1。研究GPM6样蛋白在PNS中膜蛋白酶体定位中的作用，验证我们关于PNS中NMP通过与M6a/b糖蛋白结合定位到神经元膜的假设；目标2。为了研究PNS NMP在DRG神经元发育、髓鞘形成和活动中的需求，以验证我们的假设，即PNS NMP信号是正常髓鞘形成和完全髓鞘化PNS神经元功能所必需的。目标3。研究NMP肽在轴突-胶质细胞通讯中的功能，验证我们的假设，即PNS轴突-胶质细胞通讯部分是通过NMP信号肽介导的。上述目标的完成将为进一步研究PNS中的神经元膜蛋白酶体信号提供基础。

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.