Objective: The aim of this study was to investigate the mechanism by which the lysosomal damage response (LDR) defends against the escape of α-synuclein (αSyn) aggregates from lysosomes and how this impairment contributes to the propagation of αSyn aggregation.

Background: Recently, it has been shown that extracellular protein aggregates can rupture the lysosomal membrane. It is also known that lysosomal membrane disruption induces multiple lysosomal damage responses (LDRs), including lysosomal clearance by lysophagy and lysosomal membrane repair by the ESCRT machinery. These findings led us to hypothesize that LDR would act defensively in the propagation of αSyn aggregation.

Method: Cell-based models were used to investigate the intracellular dynamics of exogenous αSyn aggregates, endogenous αSyn seeded aggregation, and the LDR. The effect of LDR dysfunction on the propagation of αSyn aggregates was also analyzed.

Results: We observed the accumulation of exogenous αSyn aggregates in lysosomes and the induction of lysosomal vesicle rupture. In addition, selective autophagy, known as lysophagy, was upregulated in response to damaged lysosomes. Cells deficient in lysophagy due to knockout of the autophagy regulator FIP200 exhibited significantly higher levels of seeded aggregation compared to wild-type cells, suggesting that lysophagy prevents the escape of aggregates and subsequent seeded aggregation. In addition, impairment of lysosomal repair by the ESCRT machinery enhanced αSyn propagation in wild-type cells but not in FIP200 knockout cells, suggesting that lysosomal repair also contributes to the defense against αSyn escape, but requires the subsequent function of lysophagy.

Conclusion: These findings highlight the protective role of the lysosomal damage response against the intracellular propagation of αSyn aggregation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-protective-role-of-lysosomal-damage-response-in-preventing-%ce%b1-synuclein-propagation/