Effects of extracellular alpha-synuclein on oligodendrocytes

Intracellular accumulations of fibrillar alpha-synuclein (a-Syn) are hallmarks of Parkinson`disease and multiple system atrophy (MSA). In MSA glial cytoplasmic inclusions originating in oligodendrocytes (ODC) are prominent. Since ODC express only small amounts of a-Syn and it is hardly detectable in the healthy human brain, it has been hypothesized that during disease progression a-Syn may be taken up from the extracellular environment. To test this hypothesis cultured ODC derived from the brains of newborn rats and OLN-93 cells, an oligodendroglial cell line, were incubated with recombinant human a-Syn. The data show that both cell types have the capability to take up and internalize a-Syn in a time- and concentration-dependent manner. ODC take up a-Syn rather rapidly within 30min and after 24h the level decreases, indicating an effective degradation system. Immunoblot analysis demonstrates that a-Syn-oligomers are formed intracellulary, but this does not exert cytotoxic effects. In OLN-93 cells small protein aggregates are visible. Membrane lipid modification by the PUFA docosahexaenoic acid augmented oligomerization of a-Syn and sensitized the cells against oxidative stress. To summarize, a-Syn is taken up by ODC from the cell culture medium, small aggregates are formed, which do not lead to cytotoxicity and cell death. Only when cells are subjected to an additional stress, such as oxidative stress, oligomerization of a-Syn is augmented and aggregates are enlarged.