Lysophagy protects against propagation of α- synuclein aggregation through ruptured lysosomal vesicles

• 成果类型: Article
• 署名作者: Kakuda, Keita; Ikenaka, Kensuke; Kuma, Akiko; Doi, Junko; Aguirre, Cesar; Wang, Nan; Ajiki, Takahiro; Choong, Chi- Jing; Kimura, Yasuyoshi; Badawy, Shaymaa Mohamed Mohamed; Shima, Takayuki; Nakamura, Shuhei; Baba, Kousuke; Nagano, Seiichi; Nagai, Yoshitaka; Yoshimori, Tamotsu; Mochizuki, Hideki
• 署名单位: University of Osaka; University of Osaka; Egyptian Knowledge Bank (EKB); Zagazig University; Nara Medical University; University of Osaka
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9374
• DOI: 10.1073/pnas.2312306120
• 发表日期: 2024-01-02
• 关键词: parkinsons-disease; autophagy; biogenesis

摘要

The neuron - to- neuronpropagation of misfolded alpha-synuclein (alpha Syn) aggregates is thought to be key to the pathogenesis of synucleinopathies. Recent studies have shown that extracellular alpha Syn aggregates taken up by the endosomal-lysosomal system can rupture the lysosomal vesicular membrane; however, it remains unclear whether lysosomal rupture leads to the transmission of alpha Syn aggregation. Here, we applied cell -based alpha Syn propagation models to show that ruptured lysosomes are the pathway through which exogenous alpha Syn aggregates transmit aggregation, and furthermore, this process was prevented by lysophagy, i.e., selective autophagy of damaged lysosomes. alpha Syn aggregates accumulated predominantly in lysosomes, causing their rupture, and seeded the aggregation of endogenous alpha Syn, initially around damaged lysosomes. Exogenous alpha Syn aggregates induced the accumulation of LC3 on lysosomes. This LC3 accumulation was not observed in cells in which a key regulator of autophagy, RB1CC1/FIP200, was knocked out and was confirmed as lysophagy by transmission electron microscopy. Importantly, RB1CC1/FIP200- deficient cells treated with alpha Syn aggregates had increased numbers of ruptured lysosomes and enhanced propagation of alpha Syn aggregation. Furthermore, various types of lysosomal damage induced using lysosomotropic reagents, depletion of lysosomal enzymes, or more toxic species of alpha Syn fibrils also exacerbated the propagation of alpha Syn aggregation, and impaired lysophagy and lysosomal membrane damage synergistically enhanced propagation. These results indicate that lysophagy prevents exogenous alpha Syn aggregates from escaping the endosomal-lysosomal system and trans -mitting aggregation to endogenous cytosolic alpha Syn via ruptured lysosomal vesicles. Our findings suggest that the progression and severity of synucleinopathies are associated with damage to lysosomal membranes and impaired lysophagy.