Increased Neuronal α-Synuclein Pathology Associates with Its Accumulation in Oligodendrocytes in Mice Modeling α-Synucleinopathies

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. The histopathological hallmark of MSA is glial cytoplasmic inclusions (GCI) within oligodendrocytes, accompanied by neuronal degeneration. MSA is a synucleinopathy, and alpha-Synuclein (alpha-Syn) is the major protein constituent of the GCI. It is unclear how the neuronal alpha-Syn protein accumulates in oligodendrocytes. We tested the hypothesis that oligodendrocytes can take up neuronal-secreted alpha-Syn as part of the pathogenic mechanisms leading to MSA. We report that increases in the degree of alpha-Syn soluble oligomers or intracellular alpha-Syn levels, enhance its secretion from cultured MN9D dopaminergic cells, stably expressing the protein. In accord, we show that primary oligodendrocytes from rat brain and oligodendroglial cell lines take-up neuronal-secreted or exogenously added alpha-Syn from their conditioning medium. This uptake is concentration-, time-, and clathrin-dependent. Utilizing the demonstrated effect of polyunsaturated fatty acids (PUFA) to enhance alpha-Syn neuropathology, we show an in vivo effect for brain docosahexaenoic acid (DHA) levels on alpha-Syn localization to oligodendrocytes in brains of a mouse model for synucleinopathies, expressing human A53T alpha-Syn cDNA under the PrP promoter. Hence, pathogenic mechanisms leading to elevated levels of alpha-Syn in neurons underlie neuronal secretion and subsequent uptake of alpha-Syn by oligodendrocytes in MSA.