ALS-linked FUS R521C disrupts arginine methylation of UBAP2L and stress granule dynamics

Abstract Mutations in the fused-in-sarcoma (FUS) gene have been linked to familial amyotrophic lateral sclerosis (fALS). FUS aggregates cytosol and associates with stress granules (SGs) pathological cases, whereas is normally found nucleus. However, little known about how mutations cause neurodegeneration ALS, which distinguished by FUS-positive inclusion granules. In this study, we investigated mechanism of abnormal cytoplasmic aggregate formation caused ALS-linked mutations. R521C interacted more ubiquitin-associated protein 2-like (UBAP2L) arginine methyltransferase 1 (PRMT1) than WT, PRMT1 UBAP2L are sequestered into R521C-positive under oxidative stress. asymmetrically demethylates UBAP2L, required for both SG assembly disassembly. Furthermore, R521C, methylation reduced, loss increases SGs These results imply that an aberrant interaction between FUS-R521C causes insufficient resulting FUS-R521C-positive remaining cytoplasm. This study could lead identification a new pathogenic therapeutic targets mutation, has associated abnormally increased interactions ALS. Graphical abstract