Objective: We aimed to clarify how exogenous αSyn aggregates interact with native αSyn in the cytoplasm and seed aggregation, and what defense mechanisms protect against this invasion.

Background: Intercellular propagation of misfolded α-Synuclein (αSyn) aggregates is thought to be the core of pathogenesis in synucleinopathies. Although recent studies have revealed the cellular uptake of extracellular αSyn aggregates via the endosomal-lysosomal pathway, it is unclear how the aggregates interact with native αSyn in the cytoplasm and propagate aggregation.

Method: We investigated intracellular dynamics of exogenous αSyn aggregates, seeded aggregation of endogenous αSyn, and cellular defending response using cell-based model. We also examined how the dysfunction of those cellular defense contribute to the propagation of αSyn aggregation.

Results: We observed that exogenous αSyn aggregates accumulated in lysosomes and induced lysosomal vesicle rupture, and endogenous seeded aggregation were initiated around ruptured lysosomes. Importantly, selective autophagy was upregulated against damaged lysosome (lysophagy), and impired lysophagy function by knocking-out autophagy regulator FIP200 significantly excerbates transmission of αSyn aggregation. These results suggests that lysophagy prevents the escape of aggregates from damaged lysosomes and subsequent seeded aggregation. In the lysophagy-deficient state, various damages to lysosomal vesicles by lysmotoropic factors, reduced lysosomal enzyme activity, and specific structural polymorphisms of αSyn fibrils dramatically exacerbated the propagation of αSyn aggregation.

Conclusion: Our results suggests that the combination of damage to lysosomal membranes and impaired lysophagy play a key role in the pathogenesis of synucleinopaties.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impaired-lysophagy-function-exacerbates-propagation-of-%ce%b1-synuclein-aggregation/