Abnormal UBA1 activity or ubiquitination causes or drives many human diseases, such as cancer, major neurodegenerative diseases, Angelman syndrome, VEXAS syndrome, and spinal muscular atrophy, as well as aging, highlighting the importance of the discovery of small-molecule modulators of UBA1 activity for research and therapeutic purposes. The gene discussed is UBA1; the disease is neurodegenerative disease.