Vimentin network dysregulation mediates neurite deficits in SNCA duplication Parkinson's patient-derived midbrain neurons.

Duplication of the SNCA gene (SNCADupl), linked to elevated levels of α-synuclein (aSyn), is a genetic cause of Parkinson's disease (PD). Our prior work with human-induced pluripotent stem cell (hiPSC)-derived midbrain neurons generated from patients with PD SNCADupl identified neuritic deficits, accompanied by decreased levels of cytoskeletal element β-tubulin-III (bTubIII). To explore mechanisms underlying these effects in SNCADupl neurons, we used CRISPR-Cas9 to generate isogenic control hiPSCs. Isogenic correction of SNCA dosage restored SNCADupl-induced neurite defects and bTubIII levels. Multi-omics analyses revealed SNCADupl-induced alterations in neuronal differentiation, with a notable down-regulation of PAX6. Moreover, SNCADupl 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 PD. Notably, targeting vimentin with okadaic acid and withaferin A restored bTubIII- and neurite-associated defects, suggesting its potential to prevent aSyn-mediated neuritic degeneration.