Aggregability of the SQSTM1/p62-based aggresome-like induced structures determines the sensitivity to parthanatos

Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) triggers a noncanonical form of programmed cell death (PCD) called parthanatos, yet the mechanisms of its induction are not fully understood. We have recently demonstrated that the aggresome-like induced structures (ALIS) composed of the auto...

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Bibliographic Details
Published in:Cell death discovery 2024-02, Vol.10 (1), p.74-74, Article 74
Main Authors: Hamano, Shuhei, Noguchi, Takuya, Asai, Yukino, Ito, Ryo, Komatsu, Ryuto, Sato, Tetsu, Inoue, Aya, Maruyama, Tomoe, Kudo, Tada-aki, Hirata, Yusuke, Shindo, Sawako, Uchida, Yasuo, Hwang, Gi-Wook, Matsuzawa, Atsushi
Format: Article
Language:English
Subjects:
631/80/458
631/80/82
Apoptosis
Autophagy
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell death
Dopamine
Dopamine D1 receptors
Levodopa
Life Sciences
Neurodegenerative diseases
Poly(ADP-ribose) polymerase
Stem Cells
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Summary:Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) triggers a noncanonical form of programmed cell death (PCD) called parthanatos, yet the mechanisms of its induction are not fully understood. We have recently demonstrated that the aggresome-like induced structures (ALIS) composed of the autophagy receptor SQSTM1/p62 and K48-linked polyubiquitinated proteins (p62-based ALIS) mediate parthanatos. In this study, we identified the D1 dopamine receptor agonist YM435 as a unique parthanatos inhibitor that acts as the disaggregating agent for the p62-based ALIS. We found that YM435 structurally reduces aggregability of the ALIS, and then increases its hydrophilicity and liquidity, which prevents parthanatos. Moreover, dopamine and L-DOPA, a dopamine precursor, also prevented parthanatos by reducing the aggregability of the ALIS. Together, these observations suggest that aggregability of the p62-based ALIS determines the sensitivity to parthanatos, and the pharmacological properties of YM435 that reduces the aggregability may be suitable for therapeutic drugs for parthanatos-related diseases such as neurodegenerative diseases.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-024-01838-2