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

Shuhei Hamano; Takuya Noguchi; Yukino Asai; Ryo Ito; Ryuto Komatsu; Tetsu Sato; Aya Inoue; Tomoe Maruyama; Tada-Aki Kudo; Yusuke Hirata; Sawako Shindo; Yasuo Uchida; Gi-Wook Hwang; Atsushi Matsuzawa

doi:10.1038/s41420-024-01838-2

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

Cell Death Discov. 2024 Feb 12;10(1):74. doi: 10.1038/s41420-024-01838-2.

Authors

Shuhei Hamano^#¹, Takuya Noguchi^#², Yukino Asai¹, Ryo Ito¹, Ryuto Komatsu¹, Tetsu Sato³, Aya Inoue¹, Tomoe Maruyama¹, Tada-Aki Kudo⁴, Yusuke Hirata¹, Sawako Shindo^{5

6}, Yasuo Uchida⁷, Gi-Wook Hwang⁵, Atsushi Matsuzawa⁸

Affiliations

¹ Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
² Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. takuya.noguchi.a7@tohoku.ac.jp.
³ Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
⁴ Division of Oral Physiology, Graduate School of Dentistry, Tohoku University, Sendai, Japan.
⁵ Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
⁶ Department of Environmental Toxicology, Meiji Pharmaceutical University, Tokyo, Japan.
⁷ Department of Molecular Systems Pharmaceutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
⁸ Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. atsushi.matsuzawa.c6@tohoku.ac.jp.

^# Contributed equally.

Abstract

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.

Abstract

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