Multimodal Proteomics Reveals Dysregulated Secretion and ECM Remodelling in Schizophrenia Patient iPSC-Derived Astrocytes

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.