Alpha-synuclein transfers from neurons to oligodendrocytes

Area of Science:

• Neuroscience
• Cell Biology
• Neurodegenerative Diseases

Background:

• The origin of alpha-synuclein (α-syn) positive inclusions in oligodendrocytes in multiple system atrophy (MSA) is unknown.
• Oligodendrocytes do not express α-syn mRNA, suggesting extracellular sources for α-syn accumulation.
• Neuron-to-neuron α-syn transfer is implicated in Parkinson's disease pathogenesis.

Purpose of the Study:

• To investigate the potential transfer of α-syn from neurons to oligodendrocytes.
• To determine if oligodendrocytes can internalize various α-syn assemblies.
• To elucidate the mechanism of α-syn uptake by oligodendrocytes.

Main Methods:

• In vitro studies exposing oligodendrocytes to monomeric, oligomeric, and fibrillar α-syn.
• In vivo studies involving direct injection of α-syn species into the mouse cortex.
• Xenotransplantation models assessing human α-syn transfer to grafted rat oligodendroglial cells in a mouse model of α-syn overexpression.

Main Results:

• Oligodendrocytes demonstrate concentration and time-dependent uptake of recombinant α-syn monomers, oligomers, and fibrils in vitro.
• α-syn uptake by oligodendrocytes in vitro is dynamin-dependent, inhibited by dynasore.
• Oligodendrocytes internalize α-syn in vivo, with direct evidence of transfer from host neurons to grafted oligodendroglial cells.

Conclusions:

• Oligodendrocytes actively internalize α-syn from extracellular sources, including neurons.
• Neuron-to-oligodendrocyte transfer of α-syn is a plausible mechanism for glial cytoplasmic inclusion formation in MSA.
• This transfer mechanism may significantly contribute to the pathogenesis and progression of MSA.