| 1 | Schizophr Bull 2016 May -1: -1 |
|---|---|
| PMID | 27242348 |
| Title | Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases. |
| Abstract | There has been intense debate over the immunological basis ofschizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) ofschizophreniaand has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement inschizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes toschizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study ofschizophreniaconducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated withschizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role inschizophreniasusceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations driveschizophreniaprogression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies inschizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | Neuropeptides 2016 Jun 57: 21-34 |
| PMID | 26988064 |
| Title | Identifying neuropeptide Y (NPY) as the main stress-related substrate of dipeptidyl peptidase 4 (DPP4) in blood circulation. |
| Abstract | Dipeptidyl peptidase 4 (DPP4; EC 3.4.14.5; CD26) is a membrane-bound or shedded serine protease that hydrolyzes dipeptides from the N-terminus of peptides with either proline or alanine at the penultimate position. Substrates ofDPP4include several stress-related neuropeptides implicated in anxiety, depression andschizophrenia. A decline ofDPP4-like activity has been reported in sera from depressed patient, but not fully characterized regardingDPP4-like enzymes, therapeutic interventions and protein. Sera from 16 melancholic- and 16 non-melancholic-depressed patients were evaluated forDPP4-like activities and the concentration of solubleDPP4protein before and after treatment by anti-depressive therapies. Post-translational modification ofDPP4亚型和degradation of NPY, Peptide YY (PYY), Galanin-like peptide (GALP), Orexin B (OrxB), OrxA, pituitary adenylate cyclase-activating polypeptide (PACAP) and substance P (SP) were studied in serum and in ex vivo human blood. N-terminal truncation of biotinylated NPY by endothelial membrane-boundDPP4versus solubleDPP4was determined in rat brain perfusates and spiked sera. 较低的DPP4activities in depressed patients were reversed by anti-depressive treatment. In sera,DPP4contributed to more than 90% of the overallDPP4-like activity and correlated with its protein concentration. NPY displayed equal degradation in serum and blood, and was equally truncated by serum and endothelialDPP4. In addition, GALP and rat OrxB were identified as novel substrates ofDPP4. NPY is the bestDPP4-substrate in blood, being truncated by soluble and membraneDPP4, respectively. The decline of solubleDPP4in acute depression could be reversed upon anti-depressive treatment. Peptidases from three functional compartments regulate the bioactivity of NPY in blood. |
| SCZ Keywords | schizophrenia |