Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease

Yuki Date, Yukiko Sasazawa, Mitsuhiro Kitagawa, Kentaro Gejima, Ayami Suzuki, Hideyuki Saya, Yasuyuki Kida, Masaya Imoto, Eisuke Itakura, Nobutaka Hattori, Shinji Saiki

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

The autophagy-lysosome pathway plays an indispensable role in the protein quality control by degrading abnormal organelles and proteins including α-synuclein (αSyn) 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 1200 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 αSyn 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.

Original languageEnglish
JournaleLife
Volume13
DOIs
Publication statusPublished - 03-07-2024

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology

Fingerprint

Dive into the research topics of 'Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease'. Together they form a unique fingerprint.

Cite this