Omics profile of iPSC-derived astrocytes from Progressive Supranuclear Palsy (PSP) patients

Abstract

Progressive Supranuclear Palsy (PSP) is a neurodegenerative tauopathy and, to date, the pathophysiological mechanisms in PSP that lead to Tau hyperphosphorylation and neurodegeneration are not clear. The development of a model using neural cell lines derived from patients has the potential to identify molecules and possible biomarkers. We developed a model of induced pluripotent stem cells iPSC-derived astrocytes to investigate the pathophysiology of PSP, particularly early events that might contribute to Tau hyperphosphorylation, applying an omics approach to detect differentially expressed genes, metabolites, and proteins, including those from the secretome. Skin fibroblasts from PSP patients and controls were reprogrammed to iPSCs, which were further differentiated into neuroprogenitor cells and astrocytes. In the 5th passage, astrocytes were harvested for total ribonucleic acid sequencing. Intracellular and secreted proteins were processed for proteomics experiments. Metabolomics profiling was obtained from supernatants only. We identified hundreds of differentially expressed genes in PSP. The main networks were related to cell cycle activation. Several proteins were found exclusively secreted by the PSP group. The cellular processes related to the cell cycle and mitotic proteins, chaperonins of the TriC/CCT pathway, and redox signaling are enriched in the secretome of the PSP group. Moreover, we found spatial segregation by PCA in the metabolomics data, indicating distinct sets of metabolites between PSP and control groups. Our iPSC-derived astrocyte model can provide distinct molecular signatures for PSP patients and it is useful to elucidate the initial stages of PSP pathogenesis.