Biomolecules & Therapeutics
Alpha-Synuclein Inclusion Formation in Human Oligodendrocytes
Ye-Seul Yoon1,2,†, Woo Jung Ahn1,2,†, Diadem Ricarte1, Darlene Ortiz1, Chan Young Shin2,3,4, Seung-Jae Lee5 and
He-Jin Lee1,2,4,*
1Department of Anatomy, Konkuk University, Seoul 05029,
2Research Institute of Medical Science, Konkuk University, Seoul 05029,
3Department of Pharmacology, Konkuk University, Seoul 05029,
4IBST, Konkuk University, Seoul 05029,
5Departments of Medicine and Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
Tel: +82-2-2030-7832, Fax: +82-2-447-5685
The first two authors contributed equally to this work.
Received: May 6, 2020; Revised: May 12, 2020; Accepted: May 20, 2020; Published online: June 15, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Multiple system atrophy (MSA) is a neurodegenerative disease characterized by presence of α-synuclein-positive inclusions in the cytoplasm of oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are considered an integral part of the pathogenesis of MSA, leading to demyelination and neuronal demise. What is most puzzling in the research fields of GCIs is the origin of α-synuclein aggregates in GCIs, since adult oligodendrocytes do not express high levels of α-synuclein. The most recent leading hypothesis is that GCIs form via transfer and accumulation of α-synuclein from neurons to oligodendrocytes. However, studies regarding this subject are limited due to the absence of proper human cell models, to demonstrate the entry and accumulation of neuronal α-synuclein in human oligodendrocytes. Here, we generated mature human oligodendrocytes that can take up neuronderived α-synuclein and form GCI-like inclusions. Mature human oligodendrocytes are derived from neural stem cells via “oligosphere” formation and then into oligodendrocytes, treating the cells with the proper differentiation factors at each step. In the final cell preparations, oligodendrocytes consist of the majority population, while some astrocytes and unidentified stem cell-like cells were present as well. When these cells were exposed to α-synuclein proteins secreted from neuron-like human neuroblastoma cells, oligodendrocytes developed perinuclear inclusion bodies with α-synuclein immunoreactivity, resembling GCIs, while the stem cell-like cells showed α-synuclein-positive, scattered puncta in the cytoplasm. In conclusion, we have established a human oligodendrocyte model for the study of GCI formation, and the characterization and use of this model might pave the way for understanding the pathogenesis of MSA.
Keywords: Alpha-synuclein, Multiple system atrophy, Oligodendrocyte, Transmission, Neurodegeneration

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