Abstract
Multiple system atrophy (MSA) is characterized by the presence of distinctive glial cytoplasmic inclusions (GCIs) within oligodendrocytes that contain the neuronal protein alpha-synuclein (aSyn) and the oligodendroglia-specific phosphoprotein TPPP/p25α. However, the role of oligodendroglial aSyn and p25α in the formation of aSyn-rich GCIs remains unclear. To address this conundrum, we have applied human aSyn (haSyn) pre-formed fibrils (PFFs) to rat wild-type (WT)-, haSyn-, or p25α-overexpressing oligodendroglial cells and to primary differentiated oligodendrocytes derived from WT, knockout (KO)-aSyn, and PLP-haSyn-transgenic mice. HaSyn PFFs are readily taken up by oligodendroglial cells and can recruit minute amounts of endogenous aSyn into the formation of insoluble, highly aggregated, pathological assemblies. The overexpression of haSyn or p25α accelerates the recruitment of endogenous protein and the generation of such aberrant species. In haSyn PFF-treated primary oligodendrocytes, the microtubule and myelin networks are disrupted, thus recapitulating a pathological hallmark of MSA, in a manner totally dependent upon the seeding of endogenous aSyn. Furthermore, using oligodendroglial and primary cortical cultures, we demonstrated that pathology-related S129 aSyn phosphorylation depends on aSyn and p25α protein load and may involve different aSyn “strains” present in oligodendroglial and neuronal synucleinopathies. Importantly, this hypothesis was further supported by data obtained from human post-mortem brain material derived from patients with MSA and dementia with Lewy bodies. Finally, delivery of haSyn PFFs into the mouse brain led to the formation of aberrant aSyn forms, including the endogenous protein, within oligodendroglia and evoked myelin decompaction in WT mice, but not in KO-aSyn mice. This line of research highlights the role of endogenous aSyn and p25α in the formation of pathological aSyn assemblies in oligodendrocytes and provides in vivo evidence of the contribution of oligodendroglial aSyn in the establishment of aSyn pathology in MSA.
Highlights
Multiple system atrophy (MSA) is a fatal, adult-onset, sporadic neurodegenerative disorder of uncertain etiology with no effective treatment [14]
By utilizing pre-formed fibrils (PFFs) of human recombinant aSyn as seeds of pathological aSyn, we show that endogenous oligodendroglial aSyn, which is almost undetectable at baseline, is a major component of the misfolded aSyn assemblies formed in immortalized oligodendroglial cell lines and primary oligodendroglial cultures
Two possible scenarios have been proposed to explain the origin of aSyn in oligodendrocytes and the mechanisms underlying aSyn accumulation in glial cytoplasmic inclusions (GCIs) present in MSA brains: either oligodendrocytes pathologically overexpress aSyn in the context of MSA [3] or they take up neuronally derived protein from their environment [13, 21, 23, 24, 48, 49, 55, 58]
Summary
Multiple system atrophy (MSA) is a fatal, adult-onset, sporadic neurodegenerative disorder of uncertain etiology with no effective treatment [14]. The origin of aSyn in oligodendrocytes of MSA patients is ambiguous, since it has been proposed that mature oligodendrocytes do not normally express this protein [9]. In vitro [13, 21, 23, 24, 48, 49] and in vivo studies [55, 58] demonstrated that exogenous recombinant or neuronally derived aSyn can be taken up by oligodendroglial cell lines, suggesting the neuron-to-glia transfer of aSyn. Recent evidence suggests that the “prion-like” transmission of misfolded aSyn may contribute to MSA disease risk [76]. Little is known regarding the mechanisms underlying the selective transmission of aSyn pathology in oligodendrocytes of MSA brains
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