Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development.

Neuron 2020 Feb 05

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Variants 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. Copyright © 2019 Elsevier Inc. All rights reserved.

Citation

Sehyoun Yoon, Euan Parnell, Maria Kasherman, Marc P Forrest, Kristoffer Myczek, Susitha Premarathne, Michelle C Sanchez Vega, Michael Piper, Thomas H J Burne, Lachlan A Jolly, Stephen A Wood, Peter Penzes. Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development. Neuron. 2020 Feb 05;105(3):506-521.e7