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

Schneider Y, Koller A, Schweigert A, Andert M, Hoffmann L, O’Brien S, Seebauer L, Plötz S, Kielkowski P, Winkler J, Schlachetzki JC, Xiang W (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Science Advances American Association for the Advancement of Science

Book Volume: 11

Article Number: eadq2742

Journal Issue: 23

DOI: 10.1126/sciadv.adq2742

Abstract

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^Duplinduced 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.

Authors with CRIS profile

Yanni Schneider Department of Molecular Neurology Aron Koller Department of Molecular Neurology Alina Schweigert Institut für Biochemie Marie Andert Department of Molecular Neurology Lukas Seebauer Medizinische Fakultät Jürgen Winkler Professur für Molekulare Neurologie Wei Xiang Department of Molecular Neurology

Involved external institutions

Ludwig-Maximilians-Universität (LMU)

Germany (DE) UC San Diego School of Medicine

United States (USA) (US)

How to cite

APA:

Schneider, Y., Koller, A., Schweigert, A., Andert, M., Hoffmann, L., O’Brien, S.,... Xiang, W. (2025). Vimentin network dysregulation mediates neurite deficits in SNCA duplication Parkinson’s patient–derived midbrain neurons. Science Advances, 11(23). https://doi.org/10.1126/sciadv.adq2742

MLA:

Schneider, Yanni, et al. "Vimentin network dysregulation mediates neurite deficits in SNCA duplication Parkinson’s patient–derived midbrain neurons." Science Advances 11.23 (2025).

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