β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1
Summary
β-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked neurodegenerative disorder caused by mutations in the WDR45 gene, yet its molecular mechanisms remain poorly understood. Here, we identify a role for WDR45 in stress granule (SG) disassembly, mediated through its phase separation with Caprin-1. We demonstrate that WDR45 forms gel-like condensates via its WD5 domain, which competitively displaces G3BP1 from Caprin-1 to promote SG disassembly. BPAN-associated WDR45 mutations impair condensate formation and Caprin-1 interaction, leading to delayed SG disassembly, which correlates with earlier disease onset. WDR45 depletion also exacerbates amyotrophic lateral sclerosis-associated pathological SGs, highlighting its broader relevance to neurodegenerative diseases. Using iPSC-derived midbrain neurons from a BPAN patient, we demonstrate delayed SG recovery, directly linking WDR45 dysfunction to neurodegeneration. These findings establish WDR45 as a critical regulator of SG dynamics, uncover a potential molecular basis of BPAN pathogenesis, and identify therapeutic targets for neurodegenerative diseases associated with SG dysregulation. © 2025. The Author(s).
| Authors | Li Y, Fang J, Ding Y, Zhang X, Liu Y, Qiu W, Xu H, Kang Y, Chen J, Gao Y, Zhao YG, Yang P, Wang B, Tian W, Chen Y, Bi W, Zhang P |
|---|---|
| Journal | Nature communications |
| Publication Date | 2025 Jun 5;16(1):5227 |
| PubMed | 40473629 |
| PubMed Central | PMC12141619 |
| DOI | 10.1038/s41467-025-60583-x |