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.
The proposed studies are designed to understand the role of the recently discovered neuronal membrane proteasome (NMP) and its resulting neuronal signaling peptides in the development, maintenance, and function of the peripheral nervous system (PNS). Through a series of biochemical, molecular, cellular and physiological experiments we plan to provide critical insights into this new modality of neuronal communication in the PNS. Given that PNS is highly sensitive to proteasome activity for normal development, signaling and human health, the understanding of novel NMP functions will unequivocally improve our understanding of the underlying mechanism regulating PNS biology in health and disease.
