Vimentin network dysregulation mediates neurite deficits in SNCA duplication Parkinson’s patient–derived midbrain neurons

作者：Yanni Schneider, Aron Koller, Alina Schweigert, Marie Andert, Laura Hoffmann, S O'Brien, Lukas Seebauer, Sonja Plötz, Pavel Kielkowski, Jürgen Winkler, Johannes C. M. Schlachetzki, Wei Xiang · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adq2742 · 被引用次数：6 · 研究领域：CRISPR and Genetic Engineering、Pluripotent Stem Cells Research、Parkinson's Disease Mechanisms and Treatments

Duplication of the SNCA gene ( SNCA Dupl ), 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 SNCA Dupl identified neuritic deficits, accompanied by decreased levels of cytoskeletal element β-tubulin-III (bTubIII). To explore mechanisms underlying these effects in SNCA Dupl neurons, we used CRISPR-Cas9 to generate isogenic control hiPSCs. Isogenic correction of SNCA dosage restored SNCA Dupl -induced neurite defects and bTubIII levels. Multi-omics analyses revealed SNCA Dupl -induced alterations in neuronal differentiation, with a notable down-regulation of PAX6. Moreover, SNCA Dupl 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.