Alpha-Synuclein Inclusion Formation in Human Oligodendrocytes

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by presence of alpha-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 alpha-synuclein aggregates in GCIs, since adult oligodendrocytes do not express high levels of alpha-synuclein. The most recent leading hypothesis is that GCIs form via transfer and accumulation of alpha-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 alpha-synuclein in human oligodendrocytes. Here, we generated mature human oligodendrocytes that can take up neuron-derived alpha-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 alpha-synuclein proteins secreted from neuron-like human neuroblastoma cells, oligodendrocytes developed perinuclear inclusion bodies with alpha-synuclein immunoreactivity, resembling GCIs, while the stem cell-like cells showed alpha-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.

Automated summary

The research established a human oligodendrocyte model for the study of GCI formation, showing that mature human oligodendrocytes can uptake neuron-derived alpha-synuclein and develop GCI-like inclusions. This model might contribute to a better understanding of the pathogenesis of Multiple System Atrophy (MSA).