The inventors surprisingly found that neural stimulation caused the synthesis and degradation of proteins into peptides which were then secreted into the cell media within minutes of stimulation by a novel neural-specific and membrane bound proteasome (neuronal membrane proteasome or NMP) that is transmembrane in nature. These secreted, activity-induced, proteasomal peptides (SNAPPs) range in size from about 500 Daltons to about 3000 Daltons. Surprisingly none of the peptides appear to be those previously known to have any neuronal function. Moreover, these SNAPPs have stimulatory activity and are heretofore a new class of signaling molecules. Moreover, the NMP appears to play a highly significant role in aspects of neuronal signaling known to be critical for neuronal function. The inventors have gone on to develop all tools to study this novel mechanisms including protocols and practice for generation and purification of SNAPPs as well as a new and specific inhibitor of the NMP allowing for selective control of this process in the nervous system. The present invention provides methods of making and using these SNAPPs for both laboratory and clinical purposes, the screening for molecules which modulate NMP function in vivo and in vitro, and methods for diagnosis of NMP related diseases.
A NOVEL NERVOUS SYSTEM-SPECIFIC TRANSMEMBRANE PROTEASOME COMPLEX THAT MODULATES NEURONAL SIGNALING THROUGH EXTRACELLULAR SIGNALING VIA BRAIN ACTIVITY PEPTIDES