Understanding the pathophysiological substrates of schizophrenia is a major challenge for current neuropsychiatric research. As part of a set of multi-omics experiments, we performed an extensive case-control proteomics study on 192 post-mortem tissue sections from prefrontal cortex from 96 individuals, including 47 cases with schizophrenia and 49 healthy controls. Using two independently measured cortical datasets, we identified 387 proteins differentially expressed between schizophrenia cases and controls at a 5% FDR threshold. This significantly regulated set of proteins contains genes located in GWAS-identified schizophrenia loci and proteins identified by pQTL analysis. Gene ontology analysis using GOAT provided evidence for regulation of several major protein categories, emphasizing downregulation of mitochondrial oxidative respiration, ribosomes and the proteasome, upregulation of kinases and (small) GTPases. SynGO analysis supports the notion of synaptic dysfunction in schizophrenia, with major regulators of pre- and postsynaptic function compromised. Our findings highlight the complex molecular dysregulation in schizophrenia, with mitochondrial function downregulated versus signaling and trafficking upregulated, and synapse function disrupted; in combination with prior avenues of research, these finding support a role for energy deficits compromising highly ATP dependent neuronal function as a target for therapeutic interventions.

Astrocytes are increasingly implicated in the pathophysiology of schizophrenia (SCZ), yet how astrocytic dysfunction contributes to disease-relevant neuronal abnormalities remains unclear. Here, we used mass spectrometry–based proteomics to profile lysates (proteome) and secreted proteins (secretome) from iPSC-derived astrocytes originating from 9 SCZ patients and 8 healthy controls. Compartment-specific analyses showed that lysates were enriched for mitochondrial and nuclear pathways, whereas astrocyte-conditioned media (ACM) were enriched for extracellular matrix (ECM) and vesicle-associated proteins. Differential expression analysis revealed minimal overlap between dysregulated proteins in lysates and ACM, suggesting modality-specific effects of SCZ-associated donor background. Interestingly, ECM proteins and key secreted cues involved in synaptic development, including MFGE8 and SEMA3C, were selectively reduced in SCZ ACM, whereas RNA-processing proteins were aberrantly increased. This is in line with previously reported microRNA enrichment in extracellular vesicles (EV) derived from SCZ patients. Gene set analyses further identified the alteration in secretion and nuclear processes as well as the potential involvement of autophagy-dependent release mechanism in SCZ astrocytes. Together, these findings suggest disrupted astrocytic protein homeostasis and extracellular signalling in SCZ iPSC-derived astrocytes, providing mechanistic insight into astrocyte-mediated contributions to synaptic and circuit deficits in the disorder.