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 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.
Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Haya
H
Kisos
Katharina
K
Pukaß
Tamir
T
Ben-Hur
Christiane
C
Richter-Landsberg
Ronit
R
Sharon
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D002966:Clathrin; D005231:Fatty Acids, Unsaturated; D051844:alpha-Synuclein; D004281:Docosahexaenoic Acids