Objective: Multiple system atrophy (MSA) is pathologically characterized by accumulation of misfolded α-synuclein (α-syn) in oligodendrocytes (OLGs), which is known as glial cytoplasmic inclusions (GCIs). Our objective is to interpret the cellular pathogenesis of MSA in association with possible pathological involvement of premature OLGs.

Background: MSA is one of the most refractory neurodegenerative diseases with no disease-modifying treatment. Previous reports have suggested that prion-like cell-to-cell propagation of pathological α-syn is possible not only in Parkinson’s disease (PD) but in MSA brains. Our previous in vitro investigation has suggested that premature OLGs can be more susceptible to the invasion of extracellular α-syn pre-formed fibrils enabling the development of pathological inclusions within OLGs (Fig. 1) (1). Nevertheless, actual involvement of premature OLGs in MSA pathology is still largely unknown.

Method: The density and morphology of premature OLGs in the brains of MSA patients (n=9) were compared with those of PD/diffuse Lewy body disease (DLB) (n=9) and non-neurodegenerative controls (n=6). The presence of pathological α-syn-immunoreactive inclusions within premature OLGs was also quantitatively analyzed by confocal microscopy. In addition, the interaction of extracellular α-syn pre-formed fibrils and premature OLGs was analyzed through experiments with primary OLG culture.

Results: Postmortem brain analysis revealed that the presence of pathological inclusions was related to impaired maturation of premature OLGs, which result is observed in the brains of MSA patients but not in those of PD/DLB and non-neurodegenerative controls. Immunofluorescence analysis by confocal microscopy revealed that some premature OLGs contained GCI-like inclusions. Experiments with primary OLG culture suggested that the premature state of OLGs potentially provides a critical period for extracellular α-syn pre-formed fibrils to invade OLG lineage cells. Moreover, the exposure of α-syn pre-formed fibrils to premature OLGs caused reduced cell viability.

Conclusion: Given that accumulating evidence suggests the presence of OLG maturation even in adult human brains, insufficient OLG maturation due to the emergence of pathological α-syn may interfere the replacement of abnormal OLGs, exacerbating the neurodegenerative state in MSA pathology.

References: 1. Kaji S, Maki T, Kinoshita H, Uemura N, Ayaki T, Kawamoto Y, et al. Pathological Endogenous alpha-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy. Stem cell reports. 2018;10(2):356-65.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/premature-state-of-oligodendrocytes-potentially-provides-critical-period-for-extracellular-pathological-%ce%b1-synuclein-to-invade-oligodendrocyte-lineage-cells/