Yoon, S.Parnell, E.Kasherman, M.Forrest, M.P.Myczek, K.Premarathne, S.Sanchez Vega, M.C.Piper, M.Burne, T.H.J.Jolly, L.A.Wood, S.A.Penzes, P.2025-07-162025-07-162020Neuron, 2020; 105(3):506-5210896-62731097-4199https://hdl.handle.net/2440/146002Variants in the ANK3 gene encoding ankyrin-G are associated with neurodevelopmental disorders, including intellectual disability, autism, schizophrenia, and bipolar disorder. However, no upstream regulators of ankyrin-G at synapses are known. Here, we show that ankyrin-G interacts with Usp9X, a neurodevelopmental-disorder-associated deubiquitinase (DUB). Usp9X phosphorylation enhances their interaction, decreases ankyrin-G polyubiquitination, and stabilizes ankyrin-G to maintain dendritic spine development. In forebrain-specific Usp9X knockout mice (Usp9X-/Y), ankyrin-G as well as multiple ankyrin-repeat domain (ANKRD)-containing proteins are transiently reduced at 2 but recovered at 12 weeks postnatally. However, reduced cortical spine density in knockouts persists into adulthood. Usp9X-/Y mice display increase of ankyrin-G ubiquitination and aggregation and hyperactivity. USP9X mutations in patients with intellectual disability and autism ablate its catalytic activity or ankyrin-G interaction. Our data reveal a DUB-dependent mechanism of ANKRD protein homeostasis, the impairment of which only transiently affects ANKRD protein levels but leads to persistent neuronal, behavioral, and clinical abnormalities.en© 2019 Elsevier Inc.ANKankyrin-Gdeubiquitinaseintellectual disabilityproximity ligation assaySHANKstructured illumination microscopyDendritic SpinesCells, CulturedAnimalsMice, Inbred C57BLMice, KnockoutHumansMiceUbiquitin ThiolesteraseAnkyrin RepeatProtein Structure, SecondaryProtein Structure, TertiaryHomeostasisMaleNeurogenesisHEK293 CellsProteostasisJournal article10.1016/j.neuron.2019.11.0032024-07-25513740Jolly, L.A. [0000-0003-4538-2658]