Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells

Schneider Y, Drobny A, Prots I, Zunke F, Xiang W, Seebauer L, Schneider Y, Drobny A, Ploetz S, Koudelka T, Tholey A, Prots I, Winner B, Zunke F, Winkler J, Xiang W (2022)

Publication Language: English

Publication Type: Journal article, Review article

Publication year: 2022

Journal

International Journal of Molecular Sciences MDPI

Book Volume: 23

Article Number: 1812

Journal Issue: 3

DOI: 10.3390/ijms23031812

Abstract

Parkinson’s disease (PD) is neuropathologically characterized by the loss of dopaminergic neurons and the deposition of aggregated alpha synuclein (aSyn). Mounting evidence suggests that neuritic degeneration precedes neuronal loss in PD. A possible underlying mechanism could be the interference of aSyn with microtubule organization in the neuritic development, as implied by sev-eral studies using cell-free model systems. In this study, we investigate the impact of aSyn on mi-crotubule organization in aSyn overexpressing H4 neuroglioma cells and midbrain dopaminergic neuronal cells (mDANs) generated from PD patient-derived human induced pluripotent stem cells (hiPSCs) carrying an aSyn gene duplication (SNCADupl). An unbiased mass spectrometric analysis reveals a preferential binding of aggregated aSyn conformers to a number of microtubule elements. We confirm the interaction of aSyn with beta tubulin III in H4 and hiPSC-derived mDAN cell model systems, and demonstrate a remarkable redistribution of tubulin isoforms from the soluble to insoluble fraction, accompanied by a significantly increased insoluble aSyn level. Concordantly, SNCA-Dupl mDANs show impaired neuritic phenotypes characterized by perturbations in neurite initiation and outgrowth. In summary, our findings suggest a mechanistic pathway, through which aSyn aggregation interferes with microtubule organization and induces neurite impairments.

Authors with CRIS profile

Yanni Schneider Department of Molecular Neurology Alice Drobny Department of Molecular Neurology Iryna Prots Professur für Stammzell-Modelle seltener neuraler Erkrankungen Friederike Zunke Juniorprofessur für Translationale Neurowissenschaften Wei Xiang Department of Molecular Neurology Lukas Seebauer Medizinische Fakultät Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen Jürgen Winkler Professur für Molekulare Neurologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

Bavarian Research Association Interaction of Human Brain Cells (ForInter) March 1, 2019 - Dec. 31, 2023 E030: Th17 and beyond: immune-mediated neurotoxicity determines onset and progression in Parkinson’s disease April 1, 2020 - March 31, 2023 E030: Th17 and beyond: immune-mediated neurotoxicity determines onset and progression in Parkinson’s disease April 1, 2020 - March 31, 2023

Involved external institutions

Christian-Albrechts-Universität zu Kiel DE Germany (DE)

How to cite

APA:

Schneider, Y., Drobny, A., Prots, I., Zunke, F., Xiang, W., Seebauer, L.,... Xiang, W. (2022). Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells. International Journal of Molecular Sciences, 23(3). https://doi.org/10.3390/ijms23031812

MLA:

Schneider, Yanni, et al. "Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells." International Journal of Molecular Sciences 23.3 (2022).

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