BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy
Abstract Multiple system atrophy (MSA) is pathologically characterized by the presence of fibrillar α-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 α-synuc...
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doaj-f29b433490d948c7880cd807b7c976542020-11-25T01:19:11ZengBMCActa Neuropathologica Communications2051-59602020-07-018111310.1186/s40478-020-00997-4BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophySeiji Kaji0Takakuni Maki1Jun Ueda2Tomoyuki Ishimoto3Yutaka Inoue4Ken Yasuda5Masanori Sawamura6Rie Hikawa7Takashi Ayaki8Hodaka Yamakado9Ryosuke Takahashi10Department of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityAbstract Multiple system atrophy (MSA) is pathologically characterized by the presence of fibrillar α-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 α-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 α-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 α-synuclein and cleaved caspase-9. Further in vitro examination indicated that the α-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 α-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 α-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 α-synuclein in vivo.http://link.springer.com/article/10.1186/s40478-020-00997-4α-SynucleinBreast cancer amplified sequence 1Glial cytoplasmic inclusionsMaturationMultiple system atrophyMyelination |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Seiji Kaji Takakuni Maki Jun Ueda Tomoyuki Ishimoto Yutaka Inoue Ken Yasuda Masanori Sawamura Rie Hikawa Takashi Ayaki Hodaka Yamakado Ryosuke Takahashi |
spellingShingle |
Seiji Kaji Takakuni Maki Jun Ueda Tomoyuki Ishimoto Yutaka Inoue Ken Yasuda Masanori Sawamura Rie Hikawa Takashi Ayaki Hodaka Yamakado Ryosuke Takahashi BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy Acta Neuropathologica Communications α-Synuclein Breast cancer amplified sequence 1 Glial cytoplasmic inclusions Maturation Multiple system atrophy Myelination |
author_facet |
Seiji Kaji Takakuni Maki Jun Ueda Tomoyuki Ishimoto Yutaka Inoue Ken Yasuda Masanori Sawamura Rie Hikawa Takashi Ayaki Hodaka Yamakado Ryosuke Takahashi |
author_sort |
Seiji Kaji |
title |
BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy |
title_short |
BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy |
title_full |
BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy |
title_fullStr |
BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy |
title_full_unstemmed |
BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy |
title_sort |
bcas1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2020-07-01 |
description |
Abstract Multiple system atrophy (MSA) is pathologically characterized by the presence of fibrillar α-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 α-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 α-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 α-synuclein and cleaved caspase-9. Further in vitro examination indicated that the α-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 α-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 α-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 α-synuclein in vivo. |
topic |
α-Synuclein Breast cancer amplified sequence 1 Glial cytoplasmic inclusions Maturation Multiple system atrophy Myelination |
url |
http://link.springer.com/article/10.1186/s40478-020-00997-4 |
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