Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 8, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-020-00997-4
Keywords
alpha-Synuclein; Breast cancer amplified sequence 1; Glial cytoplasmic inclusions; Maturation; Multiple system atrophy; Myelination; Oligodendrocytes; Oligodendrocyte precursor cells
Categories
Funding
- Japan Agency for Medical Research and Development (AMED) [18ek0109384h0001, 19ek0109384h0002]
- Kyoto University MSA Research Fund
- Japan Society for the Promotion of Science in Japan [18H06088, 19 K16915]
- Grants-in-Aid for Scientific Research [18H06088] Funding Source: KAKEN
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Multiple system atrophy (MSA) is pathologically characterized by the presence of fibrillar alpha-synuclein-immunoreactive inclusions in oligodendrocytes. Although the myelinating process of oligodendrocytes can be observed in adult human brains, little is known regarding the presence of alpha-synuclein pathology in immature oligodendrocytes and how their maturation and myelination are affected in MSA brains. Recently, breast carcinoma amplified sequence 1 (BCAS1) has been found to be specifically expressed in immature oligodendrocytes undergoing maturation and myelination. Here, we analyzed the altered dynamics of oligodendroglial maturation in both MSA brains and primary oligodendroglial cell cultures which were incubated with alpha-synuclein pre-formed fibrils. The numbers of BCAS1-expressing oligodendrocytes that displayed a matured morphology negatively correlated with the density of pathological inclusions in MSA brains but not with that in Parkinson's disease and diffuse Lewy body disease. In addition, a portion of the BCAS1-expressing oligodendrocyte population showed cytoplasmic inclusions, which were labeled with antibodies against phosphorylated alpha-synuclein and cleaved caspase-9. Further in vitro examination indicated that the alpha-synuclein pre-formed fibrils induced cytoplasmic inclusions in the majority of BCAS1-expressing oligodendrocytes. In contrast, the majority of BCAS1-non-expressing mature oligodendrocytes did not develop inclusions on day 4 after maturation induction. Furthermore, exposure of alpha-synuclein pre-formed fibrils in the BCAS1-positive phase caused a reduction in oligodendroglial cell viability. Our results indicated that oligodendroglial maturation and myelination are impaired in the BCAS1-positive phase of MSA brains, which may lead to the insufficient replacement of defective oligodendrocytes. In vitro, the high susceptibility of BCAS1-expressing primary oligodendrocytes to the extracellular alpha-synuclein pre-formed fibrils suggests the involvement of insufficient oligodendroglial maturation in MSA disease progression and support the hypothesis that the BCAS1-positive oligodendrocyte lineage cells are prone to take up aggregated alpha-synuclein in vivo.
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