Cereblon (CRBN) is a substrate recruiter for CRL4^CRBN E3 ubiquitin ligase system playing a plethora of pivotal roles for biological systems. Here, we identified DNAJB1 (DJ1) as endogenous substrate of CRBN and report how CRBN influences the aggregation and toxicity of alpha-synuclein (α-SYN) via modulation of DJ1. CRBN interferes with molecular activities of DJ1 in vitro, in cells, and in vivo resulting in a reduced disaggregation of α-SYN fibrils, increased formation of preformed fibrils (PFFs) of α-SYN, and high susceptibility of mice to MPTP and PFF-induced neurotoxicity. Depletion of Crbn improves the behavioral and biochemical responses of mice towards neurotoxic insult. Finally, we designed a peptide inhibitor to inhibit the recruitment of DJ1 to CRBN for ubiquitination, resulting in an enhanced supply of DJ1 to counteract the toxicity of aggregated α-SYN. Our data has important implications for development of CRBN-targeting therapies that could prevent or delay progression of neurodegenerative synucleinopathy.

Cereblon （CRBN） 是 CRL4^CRBN E3 泛素连接酶系统的底物募集剂，在生物系统中起着大量关键作用。在这里，我们确定 DNAJB1 （DJ1） 是 CRBN 的内源性底物，并报道了 CRBN 如何通过调节 DJ1 影响 α-突触核蛋白 （α-SYN） 的聚集和毒性。CRBN 在体外、细胞和体内干扰 DJ1 的分子活性，导致 α-SYN 原纤维的解聚减少，α-SYN 预制原纤维 （PFF） 的形成增加，以及小鼠对 MPTP 和 PFF 诱导的神经毒性的高度敏感性。Crbn 的耗竭改善了小鼠对神经毒性损伤的行为和生化反应。最后，我们设计了一种肽抑制剂来抑制 DJ1 向 CRBN 募集以进行泛素化，从而增加 DJ1 的供应以抵消聚集的 α-SYN 的毒性。我们的数据对 CRBN 靶向疗法的开发具有重要意义，这些疗法可以预防或延缓神经退行性突触核蛋白病的进展。