한빛사논문
- 조회2,040
Sehyoun Yoon1, Euan Parnell1, Maria Kasherman3,4, Marc P. Forrest1, Kristoffer Myczek1, Susitha Premarathne3, Michelle C. Sanchez Vega5, Michael Piper4,5, Thomas H.J. Burne5,6, Lachlan A. Jolly7, Stephen A. Wood3, Peter Penzes1,2,8,*
1 Department of Physiology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
2 Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
3 Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
4 The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072 Australia
5 Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
6 Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD 4076, Australia
7 Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia
*Corresponding author : Peter Penzes
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.
Keywords ; deubiquitinase; intellectual disability; proximity ligation assay; structured illumination microscopy; ankyrin-G; ANK; SHANK
논문정보
- Research article
- 2019년 12월 (BRIC 등록일 2019-12-17)
- 국외 연구진
- 생명과학 > 신경생물학
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