Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons

Huang, Hsien-Sung; Allen, J. A.; Mabb, Angela M.; King, Ian; Miriyala, Jayalakshmi; Taylor-Blake, Bonnie; Sciaky, Noah; Dutton, J. Walter; Lee, Hyeong-Min; Chen, Xin; Jin, Jian; Bridges, Arlene S.; Zylka, Mark J.; Roth, Bryan L.; Philpot, Benjamin D.

doi:10.1038/nature10726

Cited by 321 publications

(290 citation statements)

References 37 publications

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“…Several groups have attempted to reactivate the silenced paternal copy of Ube3a [74][75][76]. Large-scale small compound screening led to identification of the topoisomerase inhibitor topotecan as having the potential to activate Ube3a from the paternal allele [74,76,77].…”

Section: Research and Developmentmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity [1].Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

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Section: Research and Developmentmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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“…One therapeutic approach has been to identify proteins that are upregulated in the brains of AS mice and to then search for pharmacological agents that target the expression or activity of the up-regulated protein. An alternative approach has been to restore the expression of Ube3a in the brains of AS mice by derepressing the paternal Ube3a allele (15,16). With approaches for reversing the effects of Ube3a loss now in hand, a set of robust behavioral assays is needed to assess the efficacy with which various therapeutic agents reverse the phenotypes of AS.…”

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confidence: 99%

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

Mandel‐Brehm

Salogiannis

Dhamne

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder.Angelman syndrome | ARC | EPHEXIN5 | ultrasonic vocalizations | EEG

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“…Camptothecin can also activate an ataxia telangiectasia mutated (ATM)-and DNAdependent protein kinase (DNA-PK)-dependent transcriptional response in quiescent cells, such as neurons (28,29), likely leading to DNA breaks and transcriptionassociated DNA rearrangements (33). Finally, Top1 inhibitors can unsilence the paternal Ube3a allele in a mouse model, giving the possibility to restore functional UBE3A protein and treat Angelman syndrome (34,35). Thus, several findings on camptothecin activity not related to replicative DNA damage and cell killing of S-phase cells prompted us to define transcriptional molecular response triggered by Top1ccs and affecting HIF-1a gene activity.…”

Section: Discussionmentioning

confidence: 99%

The Natural Inhibitor of DNA Topoisomerase I, Camptothecin, Modulates HIF-1α Activity by Changing miR Expression Patterns in Human Cancer Cells

Bertozzi

Marinello

Manzo

et al. 2014

Molecular Cancer Therapeutics

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DNA topoisomerase I (Top1) inhibition by camptothecin derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of camptothecin's effects on hypoxia-inducible factor-1a (HIF-1a) activity in human cancer cells. In particular, we provide evidence that low concentrations of camptothecin, without interfering with HIF-1a mRNA levels, can reduce HIF-1a protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1a mRNA 3 0 untranslated region in camptothecin-induced impairment of HIF-1aprotein regulation, we performed microarray analysis to identify camptothecin-induced modification of microRNAs (miRNA) targeting HIF-1a mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed, demonstrating a role for miR-17-5p and miR-155 in HIF-1a protein expression after camptothecin treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1a protein regulation and activity, widening the biologic and molecular activity of camptothecin derivatives and the perspective for novel clinical interventions. Mol Cancer Ther; 13(1); 239-48. Ó2013 AACR.

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Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons

Cited by 321 publications

References 37 publications

Angelman Syndrome

Angelman Syndrome

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

The Natural Inhibitor of DNA Topoisomerase I, Camptothecin, Modulates HIF-1α Activity by Changing miR Expression Patterns in Human Cancer Cells

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