Objective: The current study focuses in elucidating the contribution of oligodendroglial-derived exosomes in the development and spread of α-Synuclein (αSyn) pathology in Multiple System Atrophy (MSA)-like experimental models.

Background: MSA is a neurodegenerative disease, mainly defined by the formation of inclusion bodies within oligodendrocytes. These inclusions consist of various aggregated proteins, the most important of which are the neuronal protein αSyn and the oligodendroglial phosphoprotein TPPP/p25α. Under physiological conditions, αSyn cannot be detected in mature oligodendrocytes, thus supporting the prevailing proposed pathogenic pathway of αSyn entering oligodendrocytes following its release by neighboring neurons. This release takes place partly via exosomes, which may act as Trojan horses facilitating the transmission of αSyn-related pathology.

Method: A comprehensive biochemical analysis of exosomes isolated from control OLN-93 rat oligodendroglial cell lines or cells stably overexpressing human αSyn or TPPP/p25α was performed. To recapitulate the pathological conditions in vitro, we incubated the cells for 48h and 8 days either with human αSyn Pre-Formed Fibrils (PFFs) or human MSA amplified brain-derived fibrils. Both PFF- and PBS-treated (control) cells were incubated with 2% FBS-exosome depleted medium for 48h and exosome-related and intracellular αSyn levels were assessed by immunoblot and confocal microscopy.

Results: Our results indicate that both αSyn and TPPP/p25α can be released via oligodendroglial exosomes. The αSyn cargo was elevated upon treatment with all aSyn fibrils, compared to that of PBS-treated exosomes. Interestingly, we detected high molecular weight αSyn species in the exosomal fraction only in the presence of MSA-amplified aSyn fibrils. Moreover, the overexpression of hαSyn or TPPP/p25α accelerated the release of αSyn-containing exosomes, following hαSyn PFF treatment.

Conclusion: Based on our findings we surmise that oligodendroglial exosomes could serve as key participants in the spread of αSyn and/or TPPP/p25α pathology in MSA. Their potential pathogenic propensity will be further investigated following their inoculation in neural and oligodendroglial cultures or in the mouse brain. If our hypothesis is proven successful, this innovative approach will pave the way for the targeting of oligodendroglial exosomes for the treatment of MSA and, potentially, as disease biomarkers.

« Back to MDS Virtual Congress 2021

MDS Abstracts - https://www.mdsabstracts.org/abstract/oligodendroglial-derived-exosomes-as-mediators-of-%ce%b1-synuclein-pathology-in-msa-like-models/