Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease
- Chiba University, Japan
- Juntendo University, Japan
- Keio University, Japan
- National Institute of Advanced Industrial Science and Technology, Japan
- University of Tsukuba, Japan
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.
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All data generated or analysed during this study are included in the manuscript and supporting files
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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.
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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Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease
eLife 13:e98649.
https://doi.org/10.7554/eLife.98649
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