Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease
Abstract
The autophagy-lysosome pathway plays an indispensable role in the protein quality control by degrading abnormal organelles and proteins including a-synuclein (aSyn) associated with the pathogenesis of Parkinson's disease (PD). However, the activation of this pathway is mainly by targeting lysosomal enzymic activity. Here, we focused on the autophagosome-lysosome fusion process around the microtubule-organizing center (MTOC) regulated by lysosomal positioning. Through high-throughput chemical screening, we identified 6 out of 1,200 clinically approved drugs enabling the lysosomes to accumulate around the MTOC with autophagy flux enhancement. We further demonstrated that these compounds induce the lysosomal clustering through a JIP4-TRPML1-dependent mechanism. Among them, the lysosomal-clustering compound albendazole promoted the autophagy-dependent degradation of Triton-X-insoluble, proteasome inhibitor-induced aggregates. In a cellular PD model, albendazole boosted insoluble aSyn degradation. Our results revealed that lysosomal clustering can facilitate the breakdown of protein aggregates, suggesting that lysosome-clustering compounds may offer a promising therapeutic strategy against neurodegenerative diseases characterized by the presence of aggregate-prone proteins.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files
Article and author information
Author details
Funding
Japan Society for the Promotion of Science London (18K15464 21K07425)
- Yukiko Sasazawa
Japan Society for the Promotion of Science London (18KK0242 18KT0027 22H02986)
- Shinji Saiki
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Li Yu, Tsinghua University, China
Version history
- Received: April 16, 2024
- Accepted: June 10, 2024
- Accepted Manuscript published: June 20, 2024 (version 1)
Copyright
© 2024, Date et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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