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.
Highlights
The accumulation of misfolded α-synuclein (α-syn) within oligodendrocytes (OLGs), known as glial cytoplasmic inclusions (GCIs), is considered to be responsible for both oligodendroglial dysfunction and neurodegeneration, which can trigger the onset of symptoms in multiple system atrophy (MSA) [21]
In the frontal cortex, compared with control brains, a trend showing an increase in breast-carcinoma amplified sequence 1 (BCAS1)(+) cell counts and a decrease in myelin basic protein (MBP)-immunoreactive area was observed in MSA brains; these differences were not statistically significant (Fig. 1 A–C)
Phosphorylated α-synuclein density negatively correlates with the numbers of BCAS1(+) cells in mature morphology in the frontal cortex of MSA brains On the basis of the observation that there is a population of differentiating OLGs immunolabeled with BCAS1 predominantly in the frontal cortex, we focused on the maturation of BCAS1(+) cells of this region in the presence of p-α-syn-immunoreactive inclusions
Summary
The accumulation of misfolded α-synuclein (α-syn) within oligodendrocytes (OLGs), known as glial cytoplasmic inclusions (GCIs), is considered to be responsible for both oligodendroglial dysfunction and neurodegeneration, which can trigger the onset of symptoms in multiple system atrophy (MSA) [21]. BCAS1-expressing (BCAS1(+)) cells represent a distinct oligodendroglial cell population that can be distinguished by the markers for OPCs and mature OLGs. while BCAS1(+) cells express OLIG2 and SOX10, human data suggest that they show limited immunolabeling with other oligodendroglial cell markers, such as neural/glial antigen 2 (NG2) (3.5%), tubulin polymerization promoting protein (TPPP/p25α) (0.6%), CC1 (0%), proteolipid protein (PLP) (0%), and myelin basic protein (MBP) (7.5%) [6]. While BCAS1(+) cells express OLIG2 and SOX10, human data suggest that they show limited immunolabeling with other oligodendroglial cell markers, such as neural/glial antigen 2 (NG2) (3.5%), tubulin polymerization promoting protein (TPPP/p25α) (0.6%), CC1 (0%), proteolipid protein (PLP) (0%), and myelin basic protein (MBP) (7.5%) [6] These cells typically display multiple symmetrically radiating processes or segments aligned in parallel. BCAS1(+) cells are known to be increased within the remyelinating areas of multiple sclerosis, suggesting that a portion of the BCAS1(+) cell population is engaged in the active regeneration of OLGs [6]
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