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

    Author(s)
    Yoon, S
    Parnell, E
    Kasherman, M
    Forrest, MP
    Myczek, K
    Premarathne, S
    Sanchez Vega, MC
    Piper, M
    Burne, THJ
    Jolly, LA
    Wood, SA
    Penzes, P
    Griffith University Author(s)
    Wood, Stephen A.
    Premarathne, Susitha
    Kasherman, Maria Addellyn A.
    Year published
    2020
    Metadata
    Show full item record
    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 ...
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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.
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    Journal Title
    Neuron
    Volume
    105
    Issue
    3
    DOI
    https://doi.org/10.1016/j.neuron.2019.11.003
    Subject
    Neurosciences
    Psychology
    Cognitive and computational psychology
    ANK
    SHANK
    ankyrin-G
    deubiquitinase
    intellectual disability
    Publication URI
    http://hdl.handle.net/10072/393544
    Collection
    • Journal articles

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