Objective: Exosomes, nano-sized extracellular vesicles, play an important role in many physiological processes in the central nervous system. Recently, we and others have demonstrated that exosomes mediate α-syn secretion. While exosomes may contribute to propagation of pathogenic proteins in neurodegenerative disorders, exosomal α-syn secretion can mitigate its accumulation in neurons. We hypothesized that exosome-mediated α-syn secretion is linked to α-syn accumulation in neurons.

Background: Pathological feature of Parkinson’s disease (PD) is the formation of Lewy bodies/neurites of which the main component is α-synuclein (α-syn). Although extensively studied, the precise mechanism of α-syn accumulation remains elucidated.

Methods: We used α-syn-inducible human neuroglioma (H4) cells and dopaminergic (DA) neurons differentiated from induced pluripotent stem cells (iPSCs) taken from the patients with SNCA triplication. The number of exosomes was measured by nanoparticle tracking analysis. The formation of intraluminal vesicles (ILVs) at multivesicular endosomes (MVEs) was analyzed by the in vitro invagination assay. We developed pHLuorin-CD63, which allows us to quantify the fusion of MVEs with plasma membrane.

Results: When α-syn expression was induced in H4 cells, the number of exosomes released in the media was decreased. However, vesicles positive for CD63, a marker of MVEs, were increased in the cells. The increased α-syn levels did not alter ILV formation, but significantly decreased fusion of MVEs with the plasma membrane, suggesting that α-syn overexpression impairs the process of exosomal secretion. Finally, we confirmed the impaired exosome secretion in SNCA triplication DA neurons.

Conclusions: These results indicate that impaired exosomal secretion by increased α-syn expression may lead to further α-syn accumulation. Targeting this pathway may provide novel therapeutic benefits in PD and associated synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-increased-%ce%b1-syn-expression-inhibits-exosomal-secretion/