| First Author | Yoon S | Year | 2020 |
| Journal | Neuron | Volume | 105 |
| Issue | 3 | Pages | 506-521.e7 |
| PubMed ID | 31813652 | Mgi Jnum | J:290391 |
| Mgi Id | MGI:6435340 | Doi | 10.1016/j.neuron.2019.11.003 |
| Citation | Yoon S, et al. (2020) Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development. Neuron 105(3):506-521.e7 |
| abstractText | 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. |
