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  Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models.

Mavroeidi, P., Arvanitaki, F., Karakitsou, A. K., Vetsi, M., Kloukina, I., Zweckstetter, M., et al. (2019). Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. Acta Neuropathologica, (in press). doi:10.1007/s00401-019-02014-y.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-77DC-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-B54A-E
Genre: Journal Article

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Mavroeidi, P., Author
Arvanitaki, F., Author
Karakitsou, A. K., Author
Vetsi, M., Author
Kloukina, I., Author
Zweckstetter, M.1, Author              
Giller, K.2, Author              
Becker, S.2, Author              
Sorrentino, Z. A., Author
Giasson, B. I., Author
Jensen, P. H., Author
Stefanis, L., Author
Xilouri, M., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              
2Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: Alpha-synuclein; Multiple system atrophy; Myelin; Oligodendrocytes; Seeding; Tubulin polymerization promoting protein
 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.

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Language(s): eng - English
 Dates: 2019-04-22
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1007/s00401-019-02014-y
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Title: Acta Neuropathologica
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: (in press) Start / End Page: - Identifier: -