Distribution and expression of neuropeptide processing enzymes in the postmortem human hippocampus

Waselus M, Lovay DN, Medina A, Burke S, Bunney WE, Myers RM, Schatzberg AF, Barchas JD, Akil H, Watson SJ
Society for Neuroscience. 2013.


The processing of neuropeptides consists of multiple steps that are essential for the conversion of inactive peptide precursors into biologically active neuropeptides. The first step in this process is carried out by proprotein convertases (PCs) that cleave inactive peptide precursors C-terminal to paired basic amino acid residues (e.g., Lys/Arg). Seven of the nine members of the PC family recognize this basic cleavage site and are responsible for the processing of a wide range of neuropeptide precursors as well as enzymes, growth factors, receptors, and signaling molecules. Two members of this family, PC1 and PC2, are active in the regulatory secretory pathway where they process peptide precursors stored in secretory granules. The activity of PC1 and PC2 can be blocked early in the secretory pathway when bound by their endogenous inhibitors proSAAS (PC1) and 7B2 (PC2). Although the distribution of the PCs and their “binding proteins” has been previously characterized in rodent brain, information regarding their expression and distribution in the human brain is limited. Thus, the current study examined the mRNA expression and distribution patterns of PC1 and PC2 as well as their binding proteins proSAAS and 7B2 in the postmortem human brain of 9 subjects with no reported history of psychiatric disorders (i.e. control subjects). Frozen 10µm sections through the posterior hippocampus of normal control subjects were processed for in situ hybridization histochemistry using radiolabeled cRNA probes for PC1, PC2, proSAAS and 7B2, and mRNA expression was subsequently measured in the dentate gyrus (DG) and CA subfields (CA1, CA2 and CA3) of this region. PC1 expression was greatest in CA3 relative to the DG and other CA subfields. For PC2, however, mRNA expression was equally abundant in the DG and CA3 regions, both of which exhibited significantly greater PC2 expression compared to the CA1 and CA2 subregions. Interestingly, the relative expression of 7B2 across posterior hippocampal subregions was similar to PC1 while the expression of proSAAS followed a pattern similar to that of PC2, which was unexpected given that proSAAS and 7B2 are involved in the inhibition of PC1 and PC2, respectively. Studies are currently underway to determine whether mRNA expression of these PCs/binding proteins is different in the posterior hippocampus of postmortem subjects diagnosed with Major Depressive Disorder (MDD) compared to control subjects. Overall, the examination of these processing enzymes in the posterior hippocampus, a brain region implicated in cognitive function, will provide a better understanding of neuropeptide processing in this region and how it relates to MDD.