Early-onset Parkinson’s disease (EOPD) is a movement disorder caused by loss of specific neurons in the midbrain that are responsible for fine motor control. Mutations in the ubiquitin ligase parkin and the kinase PINK1 (which work together to target degradation of damaged mitochondria) cause EOPD, as mitochondrial homeostasis is crucial for neuronal survival. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane, where it phosphorylates ubiquitin and ubiquitin-like (Ubl) domains. Phospho-ubiquitin (pUb) then recruits parkin to the outer mitochondrial membrane where parkin is phosphorylated. This leads to the damaged organelle being targeted for degradation. Mutations in the Ubl domain of parkin can reduce PINK1-mediated activation. Compounds that can activate parkin without the need for Ubl are therefore sought after for treatment of EOPD.

Now, Sauvé et al. have shown that a small molecule allosteric modulator can act as a molecular glue to enhance the ability of pUb to activate parkin. The small molecule (called BIO-2007817) works by gluing pUb (or pUbl) to a zinc-finger domain of parkin called RING0, thus indirectly activating parkin. Further experiments confirmed that BIO-2007817 can trigger autoubiquitination of unphosphorylated parkin lacking a Ubl, and that presence of pUb was sufficient. Crystal structure studies revealed the binding orientation of BIO-2007817, confirming the mechanism of action. Finally, in organello ubiquitination and cellular mitophagy assays show how BIO-2007817 can partially rescue pathogenic parkin mutations R42P and V56E, which are associated with EOPD. These findings could help develop therapeutics for treating EOPD, particularly that caused by mutations affecting PINK1-mediated activation of parkin.

早发性帕金森病 （EOPD） 是一种运动障碍，由中脑中负责精细运动控制的特定神经元的缺失引起。泛素连接酶 parkin 和激酶 PINK1 的突变（它们共同作用以靶向受损线粒体的降解）会导致 EOPD，因为线粒体稳态对神经元存活至关重要。线粒体损伤后，PINK1 在线粒体外膜上积累，在那里磷酸化泛素和泛素样 （Ubl） 结构域。然后，磷酸泛素 （pUb） 将 parkin 募集到线粒体外膜，parkin 被磷酸化。这导致受损的细胞器成为降解的目标。parkin 的 Ubl 结构域突变可以减少 PINK1 介导的激活。因此，无需 Ubl 即可激活 parkin 的化合物被用于治疗 EOPD。

现在，Sauvé 等人已经证明，小分子变构调节剂可以作为分子胶来增强 pUb 激活 parkin 的能力。这种小分子（称为 BIO-2007817）的工作原理是将 pUb（或 pUbl）粘附到 parkin 的锌指结构域（称为 RING0）上，从而间接激活 parkin。进一步的实验证实，BIO-2007817 可以触发缺乏 Ubl 的未磷酸化 parkin 的自泛素化，并且 pUb 的存在就足够了。晶体结构研究揭示了 BIO-2007817 的结合方向，证实了其作用机制。最后，在细胞器泛素化和细胞线粒体自噬测定中，BIO-2007817 如何部分挽救与 EOPD 相关的致病性 parkin 突变 R42P 和 V56E。这些发现可能有助于开发治疗 EOPD 的治疗方法，特别是由影响 PINK1 介导的 parkin 激活的突变引起的治疗方法。