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.

聚（ADP-核糖）聚合酶-1 (PARP-1) 的过度激活会引发一种非典型形式的程序性细胞死亡 (PCD)，称为“parthanatos”，但其诱导机制尚不完全清楚。我们最近证明，由自噬受体 SQSTM1/p62 和 K48 连接的多聚泛素化蛋白（基于 p62 的 ALIS）组成的类聚集体诱导结构（ALIS）介导parthanatos。在这项研究中，我们确定了 D1 多巴胺受体激动剂 YM435 是一种独特的 parthanatos 抑制剂，可作为基于 p62 的 ALIS 的解聚剂。我们发现YM435在结构上降低了ALIS的聚集性，然后增加了其亲水性和流动性，从而防止了parthanatos。此外，多巴胺和 L-DOPA（一种多巴胺前体）还可以通过降低 ALIS 的聚集性来预防 parthanatos。总之，这些观察结果表明，基于p62的ALIS的聚集性决定了对parthanatos的敏感性，而YM435降低聚集性的药理学特性可能适合于与parthanatos相关的疾病（例如神经退行性疾病）的治疗药物。