Akber Uroos, Jung Jun-Hyung, Yoon Heewoong, Seo Jiwon, Park Chul-Seung
Laboratory of Molecular Neurobiology, School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
Integrated Institute of Biomedical Research, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
NPJ Parkinsons Dis. 2024 Oct 23;10(1):194. doi: 10.1038/s41531-024-00801-3.
Cereblon (CRBN) is a substrate recruiter for CRL4 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.
小脑萎缩相关蛋白（CRBN）是CRL4 E3泛素连接酶系统的底物招募蛋白，对生物系统起着诸多关键作用。在此，我们鉴定出DNAJB1（DJ1）为CRBN的内源性底物，并报告了CRBN如何通过调节DJ1来影响α-突触核蛋白（α-SYN）的聚集和毒性。CRBN在体外、细胞内和体内干扰DJ1的分子活性，导致α-SYN原纤维的解聚减少、α-SYN预形成纤维（PFFs）的形成增加，以及小鼠对MPTP和PFF诱导的神经毒性高度敏感。敲除Crbn可改善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被招募至CRBN进行泛素化，从而增加DJ1的供应以抵消聚集的α-SYN的毒性。我们的数据对于开发靶向CRBN的疗法具有重要意义，这些疗法可预防或延缓神经退行性突触核蛋白病的进展。
