Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development
Date
2020
Authors
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.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Neuron, 2020; 105(3):506-521
Statement of Responsibility
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, and Peter Penzes
Conference Name
Abstract
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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2019 Elsevier Inc.