Multimodal Proteomics reveals dysregulated secretion and ECM remodeling in schizophrenia patient iPSC-derived astrocytes

ABSTRACT: Astrocytes are increasingly implicated in the pathophysiology of schizophrenia (SCZ), yet how astrocytic dysfunction contributes to disease-relevant neuronal abnormalities remains unclear. Here, we use mass spectrometry–based proteomics to profile lysates (proteome) and secreted (secretome) proteins 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) was enriched for extracellular matrix (ECM) and vesicle-associated proteins. Differential expression analysis revealed minimal overlap between dysregulated proteins in lysates and ACM, indicating modality-specific effects of SCZ genetic background. Interestingly, ECM proteins and key secreted cues involved in synaptic development, including MFGE8, 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 altered secretion-related pathways, nuclear processes, and potential involvement of autophagy-dependent release mechanisms. Together, these findings demonstrate astrocytic protein homeostasis and extracellular signaling aberrations in SCZ iPSCs, providing mechanistic insight into astrocyte-mediated contributions to synaptic and circuit deficits in the disorder.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Frank Koopmans  

LAB HEAD: August B. Smit

PROVIDER: PXD075039 | Pride | 2026-06-29

REPOSITORIES: Pride