The Latest Research for Angelman Syndrome by Ed Weeber Ph.D.

By Edwin J. Weeber, Ph.D.
BMC Neurosci. 2014 Jun 19;15:76. doi: 10.1186/1471-2202-15-76.
The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders.
Bailus BJ, Segal DJ1.

Abstract: Angelman syndrome is a monogenic neurologic disorder that affects 1 in 15,000 children, and is characterized by ataxia, intellectual disability, speech impairment, sleep disorders, and seizures. The disorder is caused by loss of central nervous system expression of UBE3A, a gene encoding a ubiquitin ligase. Current treatments focus on the management of symptoms, as there have not been therapies to treat the underlying molecular cause of the disease. However, this outlook is evolving with advances in molecular therapies, including artificial transcription factors – a class of engineered DNA-binding proteins that have the potential to target a specific site in the genome.

Results:
Here we review the recent progress and prospect of targeted gene expression therapies. Three main issues that must be addressed to advance toward human clinical trials are specificity, toxicity, and delivery.

Conclusions:
Artificial transcription factors have the potential to address these concerns on a level that meets and in some cases, exceeds, current small molecule therapies. We examine the possibilities of such approaches in the context of Angelman syndrome, as a template for other single-gene, neurologic disorders.

Overview:
Targeted gene technologies are evolving at an incredibly fast pace. This review addresses the potential of emerging techniques to target specific genes, how this technology works, and the limitations of these systems.

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J Neurosci. 2014 Mar 26;34(13):4558-66. doi: 10.1523/JNEUROSCI.1846-13.2014.
Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome.
Pignatelli M1, Piccinin S, Molinaro G, Di Menna L, Riozzi B, Cannella M, Motolese M, Vetere G, Catania MV, Battaglia G, Nicoletti F, Nisticò R, Bruno V.

Abstract:
Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that commits specific proteins to proteasomal degradation. How this defect causes autism and other pathological phenotypes associated with AS is unknown.

Long-term depression (LTD) of excitatory synaptic transmission mediated by type 5 metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of Ube3A(m-/p+) mice, which model AS. No changes were found in NMDA-dependent LTD induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was sensitive to the protein synthesis inhibitor anisomycin, and relied on the same signaling pathways as in wild-type mice, e.g., the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation of MAPK and PI3K nor the increase in Arc (activity-regulated cytoskeleton-associated protein) levels in response to mGlu5 receptor activation were abnormal in hippocampal slices from AS mice compared with wild-type mice. mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS mice showed a reduced expression of the short Homer protein isoform Homer 1a, and an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the hippocampus.

These findings support the link between Homer proteins and monogenic autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.

Overview:
This article exemplifies the fact that we can still learn much about molecular changes in the Angelman brain using an animal model. Here the authors show that another important receptor, the metabotropic glutamate receptor (mGluR), has altered function. These receptors are “modifiers” of the synapse and have been implicated in numerous neuropsychiatric disorders, in particular, schizophrenia. The mGluRs are different from receptors you have already heard about; NMDA and AMPA receptors. NMDA and AMPA receptors are activated by glutamate, but are ion channels, which means they allow sodium and calcium to enter the post synaptic neuron. The mGluRs are signaling receptors that also bind glutamate, but then they can activate other proteins on the inside of the cell.
In essence, these are slower acting receptors that support the faster acting AMPA and NMDA receptors (even though all these receptors are activated by the same glutamate signal), so they are considered “modifiers” of synaptic function.