Modeling of Pontocerebellar Hypoplasia Type 1B and Chemical Mimicry in Patient-Derived Neural Stem Cells

Pontocerebellar Hypoplasia 1B (PCH1B) patients exhibit profound underdevelopment of the neocerebellum and its adjacent structures, leading to severe developmental delays as well as poor survival. Here, we report a new case of PCH1B with a known mutation in EXOSC3, a component of the RNA exosome. We reprogrammed blood from the PCH1B patient and the healthy carrier parents into human induced pluripotent stem cells and differentiated these cells into neural stem cells (NSCs). Proteomic content was analyzed by mass spectrometry to reveal a slight underexpression of mutated EXOSC3 in the PCH1B patient. We discovered that several processes implicated in cell differentiation were impaired. NSCs from the mother were incubated with ERD03, a small molecule rationally developed to model PCH1B in zebrafish and analyzed by high-throughput mass spectrometry-based proteomics. In addition to affecting individual protein expression, we demonstrated the ability of the compound ERD03 to mimic PCH1B-induced protein pathways.