β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1

• Published in: Nature communications Vol. 16; no. 1; pp. 5227 - 18
• Main Authors: Li, Yin, Fang, Jie, Ding, Yuqi, Zhang, Xilong, Liu, Ying, Qiu, Wanting, Xu, He, Kang, Yunzhe, Chen, Jiayu, Gao, Yanyan, Zhao, Yan G., Yang, Peiguo, Wang, Bo, Tian, Wenmin, Chen, Yang, Bi, Wenjian, Zhang, Peipei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/109; 13/51; 14/1; 14/19; 14/35; 14/63; 38/89; 631/337/1645; 631/57/2269; 631/80/304; 692/699/375/365; 82/58; 82/83; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Condensates; Dismantling; DNA Helicases; Granular materials; HEK293 Cells; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Mesencephalon; Mice; Molecular modelling; multidisciplinary; Mutation; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurons - metabolism; Pathogenesis; Phase Separation; Poly-ADP-Ribose Binding Proteins - genetics; Poly-ADP-Ribose Binding Proteins - metabolism; Proteins; RNA Helicases - genetics; RNA Helicases - metabolism; RNA Recognition Motif Proteins - genetics; RNA Recognition Motif Proteins - metabolism; Science; Science (multidisciplinary); Stress Granules - metabolism; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-60583-x

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. BPAN is a rare neurodegenerative disease caused by WDR45 mutations. Here, the authors discover that WDR45 can competitively displace G3BP1 from Caprin-1 to promote stress granule disassembly, a function that is disrupted by BPAN-associated WDR45 mutations.