Y. WAN, E. Cordes, W. Feng, S. I. Lee, K. Munechika, Y. Sun, Z. Gao, B. Gao, J. Zhu, M. Y. Wong, K. Norman, S. Wang, h. chen, B. Liu, Z. Li, M. Srinivasan, S. Amin, X. Wei, S.-A. Mok, R. Shen, W. Luo, S. Gong, H. Li, H. Yu, L. Gan
UFMylation, a ubiquitin-like protein modification, drives tau spread through the brain, but what keeps this process in check has remained unclear. We show that TRAPPC8 acts as a natural brake on UFMylation, binding directly to the E1 enzyme UBA5 to dampen pathway activity. In Alzheimer's disease brain tissue, TRAPPC8 is reduced while UFMylation is elevated, suggesting this brake fails as disease progresses. Sustaining UFMylation in human iPSC-derived neurons increased tau aggregation and spread while disrupting lysosomal function and lipid balance. Restoring TRAPPC8-UBA5 binding reversed these defects through the lysosomal protein CLN8, which restored lysosomal function and reduced tau pathology. Notably, expressing just the UBA5-binding region of TRAPPC8 was enough to suppress tau pathology in vivo, marking it as a promising therapeutic target.