The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders

Jolly, Lachlan A.; Kumar, Raman; Penzes, Peter; Piper, Michael; Gécz, Jozef

doi:10.1016/j.biopsych.2022.03.022

Cited by 16 publications

(9 citation statements)

References 121 publications

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“…8B, Supplementary Table 2A). Among the top 40 affected genes were 23 genes linked to neuronal functions, behavior, or neurodevelopmental disorders (GeneIDs are detailed in Supplementary Table 2, sheet A): Ap2a1 (Vrahatis et al 2020), Cers1 (Godeiro Junior et al 2018), Gdf1 (Lee 1991), Hspbp1 (Jing et al 2021), Fip1l1 (Tennenbaum et al 2021), Msi2 (Luan et al 2016), Ssbp1 (Meunier et al 2021), Tmx3 (Chao et al 2010), Tmem179 (Carpanini et al 2017), Usp20 (Jolly et al 2022), Hspb11 (Shields et al 2019), Ints1 (Zhang et al 2020), P4htm (Kraatari-Tiri et al 2022), Atp13a2 (Pan & Yue 2014), Ccdc120 (Abidi et al 2016), Dpp3 (Ren et al 2021), Fam69b (Dudkiewicz et al 2013), Fbxo31 (Vadhvani et al 2013), Prr7 (Lee et al 2018), Rabac1 (Fenster et al 2000), Neurl4 (Imai et al 2015), Slc35a2 (Vals et al 2019), and Smpd1 (Alcalay et al 2019).…”

Section: Resultsmentioning

confidence: 99%

Repeated exposure to high-THCCannabissmoke during gestation alters sex ratio, behavior, and amygdala gene expression of Sprague Dawley rat offspring

Sandini

Onofrychuk

Roebuck

et al. 2023

Preprint

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Due to the recent legalization of Cannabis in many jurisdictions and the consistent trend of increasing THC content in Cannabis products, there is an urgent need to understand the impact of Cannabis use during pregnancy on fetal neurodevelopment and behavior. To this end, we repeatedly exposed female Sprague-Dawley rats to Cannabis smoke from gestational days 6 to 20 (n=12; Aphria Mohawk; 19.51% THC, <0.07% cannabidiol) or room-air as a control (n=10) using a commercially available system. Maternal reproductive parameters, behavior of the adult offspring, and gene expression in the offspring amygdala were assessed. Body temperature was decreased in dams following smoke exposure and more fecal boli were observed in the chambers before and after smoke exposure in those dams exposed to smoke. Maternal weight gain, food intake, gestational length, litter number, and litter weight were not altered by exposure to Cannabis smoke. A significant increase in the male-to-female ratio was noted in the Cannabis-exposed litters. In adulthood, both male and female Cannabis smoke-exposed offspring explored the inner zone of an open field significantly less than control offspring. Gestational Cannabis smoke exposure did not affect behavior on the elevated plus maze test or social interaction test in the offspring. Cannabis offspring were better at visual pairwise discrimination and reversal learning tasks conducted in touchscreen-equipped operant conditioning chambers. Analysis of gene expression in the adult amygdala using RNAseq revealed subtle changes in genes related to development, cellular function, and nervous system disease in a subset of the male offspring. These results demonstrate that repeated exposure to high-THC Cannabis smoke during gestation alters maternal physiological parameters, sex ratio, and anxiety-like behaviors in the adulthood offspring.

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Section: Resultsmentioning

confidence: 99%

Repeated exposure to high-THCCannabissmoke during gestation alters sex ratio, behavior, and amygdala gene expression of Sprague Dawley rat offspring

Sandini

Onofrychuk

Roebuck

et al. 2023

Preprint

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“…Substrate ubiquitination is regulated by ubiquitin ligases, which catalyze the covalent attachment of the 76 amino acid-small ubiquitin protein to specific substrates, and deubiquitinases, which catalyze the removal of ubiquitin from specific substrates. Although ubiquitin ligases have been extensively studied for their roles in neurodevelopment 5 , the functions of most deubiquitinases in the nervous system have remained largely unexplored 6 , despite their implications in neurodevelopmental disorders in genetic association studies 7 . We herein characterized the role of the deubiquitinase ubiquitin specific protease 7 (USP7) in the mammalian brain.…”

Section: Introductionmentioning

confidence: 99%

The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway

Chen,

Ferguson,

Mitchell

et al. 2023

Preprint

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The development of the brain relies on precise control of protein ubiquitination and degradation, and hence, deregulation of ubiquitination signaling networks is thought to play an important role in neurological disorders. Mutation or deletion of the deubiquitinase USP7 causes the Hao-Fountain syndrome, characterized by developmental delay, intellectual disability, autism, and aggressive behavior. Although USP7 function has been studied in proliferating cells in the context of cancer biology, the roles and mechanisms of USP7 in post-mitotic neurons have remained largely unknown. Here, we report that conditional deletion of USP7 in excitatory glutamatergic neurons in the mouse forebrain triggers diverse phenotypes in adult mice including sensory and motor deficits, learning and memory impairment, and aggressive behavior, resembling the clinical features of the Hao-Fountain syndrome. In developmental analyses of the cerebral cortex, USP7 deletion induces neuronal apoptosis, which is rescued by loss of the tumor suppressor protein p53, an established downstream mediator of USP7 signaling. However, most of the behavior abnormalities in USP7 conditional mice are not rescued by loss of p53. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Through a combination of comprehensive interaction and TMT-proteomics as well as ubiquitin biochemistry assays, we identify the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of conditional knockout of USP7 on dendritic spine morphogenesis. Collectively, our findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of the Hao-Fountain syndrome.

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“…DUBs (deubiquitinating enzymes) are a subclass of proteases that can remove ubiquitin tags from ubiquitinated proteins. 5 DUBs are important regulators of carcinogenesis and cancer development, including ovarian cancer. Ubiquitin-specific peptidase 21 (USP21) is an effective enzyme that is crucial for signal transduction, apoptosis, and DNA repair due to the stability of its substrate.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of USP21 leads to ovarian carcinoma cell death by suppressing MAPK signaling

Sun,

Yu,

Cui

et al. 2023

Biotech and App Biochem

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Ovarian cancer is the most aggressive and lethal of all gynecologic malignancies. Although the overexpression (OE) of ubiquitin‐specific peptidase 21 (USP21) has been observed in multiple cancers, its expression profile and biological function in ovarian cancer remain unknown. The expression levels of USP21 in ovarian cancer cells and tissues as well as adjacent normal tissues were assessed by qRT‐PCR or Western blot assay. The biological function of USP21 in ovarian cancer cells was assessed by cell growth assay in vitro and a tumor growth model in vivo. Our study revealed that USP21 was markedly elevated in ovarian carcinoma tissues compared with adjacent normal tissues. Downregulation of USP21 attenuated the expression levels of MEK2 and p‐ERK1/2. Depletion of USP21 resulted in suppressed cell growth of ovarian cancers in vitro and inhibited tumor growth in vivo. Conversely, OE of USP21 promoted the cell proliferation of ovarian cancers and conferred resistance to BAY 11‐7082. These findings provide evidences supporting the notion of USP21 as a promising therapeutic target for the treatment of ovarian cancer.

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The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders

Cited by 16 publications

References 121 publications

Repeated exposure to high-THCCannabissmoke during gestation alters sex ratio, behavior, and amygdala gene expression of Sprague Dawley rat offspring

Repeated exposure to high-THCCannabissmoke during gestation alters sex ratio, behavior, and amygdala gene expression of Sprague Dawley rat offspring

The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway

Inhibition of USP21 leads to ovarian carcinoma cell death by suppressing MAPK signaling

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