@article{laferriere_overexpression_2020,
	title = {Overexpression of α-Synuclein by Oligodendrocytes in Transgenic Mice Does Not Recapitulate the Fibrillar Aggregation Seen in Multiple System Atrophy},
	volume = {9},
	rights = {http://creativecommons.org/licenses/by/3.0/},
	url = {https://www.mdpi.com/2073-4409/9/11/2371},
	doi = {10.3390/cells9112371},
	abstract = {The synucleinopathy underlying multiple system atrophy ({MSA}) is characterized by the presence of abundant amyloid inclusions containing fibrillar \α-synuclein (\α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinson\’s disease ({PD}) where the pathological \α-syn aggregates are almost exclusively neuronal, the \α-syn inclusions in {MSA} are principally observed in oligodendrocytes ({OLs}) where they form glial cytoplasmic inclusions ({GCIs}). This is intriguing because differentiated {OLs} express low levels of \α-syn, yet pathogenic amyloid \α-syn seeds require significant amounts of \α-syn monomers to feed their fibrillar growth and to eventually cause the buildup of cytopathological inclusions. One of the transgenic mouse models of this disease is based on the targeted overexpression of human \α-syn in {OLs} using the {PLP} promoter. In these mice, the histopathological images showing a rapid emergence of S129-phosphorylated \α-syn inside {OLs} are considered as equivalent to {GCIs}. Instead, we report here that they correspond to the accumulation of phosphorylated \α-syn monomers/oligomers and not to the appearance of the distinctive fibrillar \α-syn aggregates that are present in the brains of {MSA} or {PD} patients. In spite of a propensity to co-sediment with myelin sheath contaminants, the phosphorylated forms found in the brains of the transgenic animals are soluble (\>80\%). In clear contrast, the phosphorylated species present in the brains of {MSA} and {PD} patients are insoluble fibrils (\>95\%). Using primary cultures of {OLs} from {PLP}-\αSyn mice we observed a variable association of S129-phosphorylated \α-syn with the cytoplasmic compartment, the nucleus and with membrane domains suggesting that {OLs} functionally accommodate the phospho-\α-syn deriving from experimental overexpression. Yet and while not taking place spontaneously, fibrillization can be seeded in these primary cultures by challenging the {OLs} with \α-syn preformed fibrils ({PFFs}). This indicates that a targeted overexpression of \α-syn does not model {GCIs} in mice but that it can provide a basis for seeding aggregation using {PFFs}. This approach could help establishing a link between \α-syn aggregation and the development of a clinical phenotype in these transgenic animals.},
	pages = {2371},
	number = {11},
	journaltitle = {Cells},
	author = {Laferrière, Florent and He, Xin and Zinghirino, Federica and Doudnikoff, Evelyne and Faggiani, Emilie and Meissner, Wassilios G. and Bezard, Erwan and De Giorgi, Francesca and Ichas, François},
	urldate = {2021-01-13},
	date = {2020-11},
	langid = {english},
	note = {Number: 11
Publisher: Multidisciplinary Digital Publishing Institute},
	keywords = {{GCIs}, multiple system atrophy, peer-reviewed, α-synuclein},
}