Trends in Neurosciences
ReviewAngelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes
Section snippets
Introduction to Angelman syndrome
Angelman Syndrome (AS) was originally described by Harry Angelman in 1965 and occurs in approximately one out of every 12,000 births 1, 2. Patients with AS exhibit developmental delay, speech impairments, intellectual disability, epilepsy, abnormal EEGs (electroencephalograms), puppet-like ataxic movements, prognathism, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity [3]. Moreover, patients with AS often exhibit socialization and communication deficits that
Monitoring neuronal UBE3A imprinting
The genomic region spanning UBE3A, the UBE3A antisense transcript (UBE3A-ATS), and the spliceosomal protein SNRPN (small nuclear ribonucleoprotein polypeptide N) [27] contains a large number of imprinted genes that are either paternally or maternally expressed in the human brain [27]. Mice possess a chromosomal region that is syntenic to human 15q11-q13 in which orthologous genes, including Ube3a, are also imprinted 28, 29, 30. UBE3A is expressed from the maternal allele in most neurons, while
AS mouse models recapitulate many AS patient phenotypes
To date, three AS mouse models have been engineered with targeted mutations that mimic de novo chromosomal abnormalities underlying AS (Table 1). Because brain-specific paternal imprinting of Ube3a also occurs in mice, all three models are based on the maternal inheritance of a chromosomal deletion that includes Ube3a. Importantly, these models recapitulate the loss of UBE3A in neurons in the central nervous system (CNS) 45, 46, 47 and display several AS-relevant phenotypes 48, 49, 50.
Changes in neuronal morphology in AS mouse models
To help understand the profound neurological deficits underlying AS, researchers have explored neuroanatomical correlates of abnormal connectivity and synaptic development in Ube3am−/p+ mice. These studies have almost exclusively focused on measuring dendritic spines at the single-cell level owing to the fact that in vivo, UBE3A is localized to postsynaptic compartments in addition to the nucleus [44]. Dendritic spine density (∼15-20%) and length (∼10-15%) are reduced in post-adolescent Ube3a
Changes in synaptic plasticity in AS mouse models
Early investigations of altered synaptic plasticity in Ube3am−/p+ mice were inspired by findings of impaired contextual fear conditioning, which led to studies of whether long-term potentiation (LTP) of Schaffer collateral synapses in the CA1 hippocampal region was impaired. Standard high-frequency stimulation protocols evoke only a transient potentiation of these synapses in hippocampal slices from Ube3am−/p+ mice [48]. However, sustained LTP, similar to what was observed typically in
Identification of brain substrates for UBE3A
UBE3A is a HECT E3 ubiquitin ligase that ubiquitinates protein substrates, leading to their degradation by the ubiquitin proteasome system (UPS) 74, 75. Multiple mutations in UBE3A have been attributed to defective UBE3A stability or catalytic function 23, 76. The ubiquitination and degradation of p53, the first identified substrate of UBE3A 77, 78, require not only UBE3A, but a viral cofactor E6, hence the initial naming of UBE3A as an E6-associated protein (E6-AP) 77, 78, 79, 80. Notably, E6
Conclusions and future directions
Although research is beginning to unveil the connections between UBE3A function and AS, there are still fundamental questions that remain to be answered (Box 1). For instance, does the UBE3A antisense mechanism fully account for why UBE3A is epigenetically silenced in the brain but not other tissues? If yes, can expression of the functionally intact, but epigenetically silenced, paternal UBE3A allele be upregulated by pharmacological means or by genetically manipulating UBE3A-ATS transcription?
Acknowledgements
We would like to thank Kathryn Condon, Yong-hui Jiang, Ian King, Anne West, and Jason Yi for critical reading of the manuscript. B.D.P. is supported by the Angelman Syndrome Foundation and the National Eye Institute (R01EY018323), and B.D.P. and M.J.Z. are supported by the Simons Foundation. Work in M.J.Z.’s laboratory is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS060725, R01NS067688). A.M.M. is supported by a Ruth L. Kirschtein National Research
Glossary
- Allele
- One of two or more forms of a given DNA sequence of a gene.
- Genomic Imprinting
- A genetic process whereby genes are differentially expressed depending on their parent-of-origin inheritance.
- Context-dependent fear conditioning
- A behavioral paradigm where animals learn to fear a neutral stimulus when paired with a noxious or painful stimulus. Brain regions involved include the amygdala and, when cued by spatial context, the hippocampus.
- Epigenetic
- Heritable and reversible modifications to
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These authors contributed equally to this work.