Alpha synuclein-mediated cytoskeletal dysfunction impairs myelination in human oligodendrocytes

Wihan J, Battis K, Hoffmann A, Windener F, Himmler M, Varghese A, Koller A, Karnatz I, Schubert DW, Zunke F, Xiang W, Kuhlmann T, Winkler J (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Acta Neuropathologica Springer

Book Volume: 150

Article Number: 33

Issue: 1

DOI: 10.1007/s00401-025-02933-z

Abstract

Oligodendroglial alpha-synuclein (aSyn) deposits are a key feature in the atypical parkinsonian disorder, multiple system atrophy (MSA) linked to profound myelin loss and neurodegeneration while precise cellular and molecular mechanisms remain unclear. We generated human oligodendrocytes (hOLs) from induced pluripotent stem cells to investigate the impact of aSyn on oligodendroglial morphology, differentiation, and function. We observed an aSyn-induced myelinogenic dysfunction characterized by impaired oligodendroglial process outgrowth, altered cell shape, and increased perinuclear accumulation of the tubulin polymerization promoting protein TPPP/p25α. These changes were associated with a reduced capacity to ensheath axons and were linked to compromised actin remodeling machinery. Actin imbalances were confirmed in post-mortem putaminal tissue from MSA patients. Treatment with a rho-associated protein kinase inhibitor rescued oligodendroglial process formation and improved ensheathment in aSyn-expressing hOLs. Our work emphasizes the aSyn-mediated interference with actin dynamics as a key pathogenic mechanism in MSA, pointing toward a novel therapeutic target for improving myelin maintenance.

Authors with CRIS profile

Jeanette Wihan Professur für Molekulare Neurologie Kristina Battis Department of Molecular Neurology Alana Hoffmann Department of Molecular Neurology Marcus Himmler Institute of Manufacturing Technology (LFT) Anish Varghese Department of Molecular Neurology Aron Koller Department of Molecular Neurology Dirk Schubert Lehrstuhl für Werkstoffwissenschaften (Polymerwerkstoffe) (LSP) Friederike Zunke Professur für Translationale Neurowissenschaften Wei Xiang Department of Molecular Neurology Jürgen Winkler Professur für Molekulare Neurologie

Additional Organisation(s)

Lehrstuhl für Werkstoffwissenschaften (Polymerwerkstoffe) (LSP)

Involved external institutions

Universitätsklinikum Münster DE Germany (DE) Universität des Saarlandes (UdS) DE Germany (DE)

How to cite

APA:

Wihan, J., Battis, K., Hoffmann, A., Windener, F., Himmler, M., Varghese, A.,... Winkler, J. (2025). Alpha synuclein-mediated cytoskeletal dysfunction impairs myelination in human oligodendrocytes. Acta Neuropathologica, 150. https://doi.org/10.1007/s00401-025-02933-z

MLA:

Wihan, Jeanette, et al. "Alpha synuclein-mediated cytoskeletal dysfunction impairs myelination in human oligodendrocytes." Acta Neuropathologica 150 (2025).

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