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Generation of Human Neurons and Oligodendrocytes from Pluripotent Stem Cells for Modeling Neuron-Oligodendrocyte Interactions
Published on: November 9, 2020
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Alpha synuclein-mediated cytoskeletal dysfunction impairs myelination in human oligodendrocytes
Jeanette Wihan1,2, Kristina Battis3, Alana Hoffmann3,4,5
1Division of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, 91054, Erlangen, Germany. jeanette.wihan@ibmt.fraunhofer.de.
Acta Neuropathologica
|September 20, 2025
Summary
Alpha-synuclein (aSyn) deposits in oligodendrocytes cause myelin loss in multiple system atrophy (MSA). This study reveals aSyn disrupts actin dynamics, impairing myelin maintenance and offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Oligodendroglial alpha-synuclein (aSyn) deposits are central to multiple system atrophy (MSA), a disorder causing myelin loss and neurodegeneration.
- The precise mechanisms linking aSyn to these pathological features remain largely unknown.
Purpose of the Study:
- To investigate the impact of aSyn on human oligodendrocytes (hOLs) derived from induced pluripotent stem cells.
- To elucidate the cellular and molecular mechanisms underlying aSyn-induced myelinogenic dysfunction in MSA.
Main Methods:
- Generation of human oligodendrocytes (hOLs) from induced pluripotent stem cells.
- Assessment of oligodendroglial morphology, differentiation, and function in the presence of aSyn.
- Analysis of actin remodeling machinery and TPPP/p25α localization.
- Examination of post-mortem MSA patient tissue.
- Pharmacological intervention using a rho-associated protein kinase inhibitor.
Main Results:
- aSyn induced myelinogenic dysfunction in hOLs, characterized by impaired process outgrowth and altered cell shape.
- Increased perinuclear accumulation of TPPP/p25α and compromised actin remodeling were observed.
- Reduced axonal ensheathment capacity was linked to actin imbalances, confirmed in MSA patient tissue.
- Rho-kinase inhibition rescued oligodendroglial process formation and improved axonal ensheathment.
Conclusions:
- aSyn interferes with actin dynamics, representing a key pathogenic mechanism in MSA.
- This disruption compromises myelin maintenance and oligodendroglial function.
- Targeting actin dynamics presents a novel therapeutic strategy for MSA aimed at improving myelin repair.
