The authors' prior work with human-induced pluripotent stem cell-derived midbrain neurons generated from patients with Parkinson disease identified neuritic deficits, accompanied by decreased levels of cytoskeletal element -tubulin-III. To explore mechanisms underlying these effects in neurons, the authors used CRISPR-Cas9 to generate isogenic control hiPSCs. Isogenic correction of dosage restored -induced neurite defects and bTubIII levels. Multi-omics analyses revealed -induced alterations in neuronal differentiation, with a notable down-regulation of PAX6. Moreover, induced an up-regulation of vimentin. Further characterization revealed heightened vimentin truncation associated with altered distribution and organization. Similar changes in vimentin levels and truncation were observed in postmortem putamen tissue from patients with sporadic Parkinson disease.
