Abstract
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 α-Synuclein (α-Syn) is the major protein constituent of the GCI. It is unclear how the neuronal α-Syn protein accumulates in oligodendrocytes. We tested the hypothesis that oligodendrocytes can take up neuronal-secreted α-Syn as part of the pathogenic mechanisms leading to MSA. We report that increases in the degree of α-Syn soluble oligomers or intracellular α-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 α-Syn from their conditioning medium. This uptake is concentration-, time-, and clathrin-dependent. Utilizing the demonstrated effect of polyunsaturated fatty acids (PUFA) to enhance α-Syn neuropathology, we show an in vivo effect for brain docosahexaenoic acid (DHA) levels on α-Syn localization to oligodendrocytes in brains of a mouse model for synucleinopathies, expressing human A53T α-Syn cDNA under the PrP promoter. Hence, pathogenic mechanisms leading to elevated levels of α-Syn in neurons underlie neuronal secretion and subsequent uptake of α-Syn by oligodendrocytes in MSA.
Highlights
Multiple system atrophy (MSA) is an adult-onset, progressive, neurodegenerative disorder with clinical symptoms of autonomic failure and motor impairment
Utilizing A53T a-Syn transgenic mice, we further show that enhances in a-Syn neuropathology, obtained by alterations in dietary brain docosahexaenoic acid (DHA) levels, modulate the degree of aSyn protein detected in oligodendrocytes
We have shown that membrane polyunsaturated fatty acids (PUFA) composition and clathrin mediated endocytosis (CME) are affected by exposure of cultured cells to physiological concentrations of PUFAs [36,39]
Summary
Multiple system atrophy (MSA) is an adult-onset, progressive, neurodegenerative disorder with clinical symptoms of autonomic failure and motor impairment. A growing body of evidence suggests that a-Syn is released from healthy neurons. A-Syn is detected in cerebrospinal fluid (CSF) [14], plasma [15], red blood cells [16,17] and skin fibroblasts [18]. While it is currently unclear whether neuronal secreted a-Syn may be used to discriminate healthy and PD-patients, the occurrence of a-Syn in blood and plasma may potentially explain its presence and toxicity in melanomas [19,20] and the epidemiological findings suggesting increased incidents of melanoma among people with PD [21]
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