Introduction: 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. In some brain areas, Tau pathology in glial cells appears to precede Tau aggregation in neurons. The development of a model using astrocyte cell lines derived from patients has the potential to identify molecules and pathways that contribute to early events of neurodegeneration. 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 omics approach to detect differentially expressed genes, metabolites, and proteins, including those from the secretome.
Methods: Skin fibroblasts from PSP patients (without MAPT mutations) and controls were reprogrammed to iPSCs, further differentiated into neuroprogenitor cells (NPCs) and astrocytes. In the 5th passage, astrocytes were harvested for total RNA sequencing. Intracellular and secreted proteins were processed for proteomics experiments. Metabolomics profiling was obtained from supernatants only.
Results: We identified hundreds of differentially expressed genes. The main networks were related to cell cycle re-activation in PSP. Several proteins were found exclusively secreted by the PSP group. The cellular processes related to the cell cycle and mitotic proteins, TriC/CCT pathway, and redox signaling were enriched in the secretome of PSP. Moreover, we found distinct sets of metabolites between PSP and controls.
Conclusion: 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.
Keywords: Astrocytes; Cell cycle; Metabolomics; Progressive supranuclear palsy; Proteomics; Tauopathy; Transcriptomics; iPSC.
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