Angelman syndrome (AS) is a rare neurogenetic disease with an estimated prevalence of one in 10,000 to 20,000 births. It is characterized by cognitive, developmental and autism-like deficits, including speech impediments, disturbed sleep, seizures, jerky movements, frequent laughter or smiling and, usually, a happy disposition. It is caused by a dysfunctional maternally inheritedUbe3A gene. The gene’s encoded protein, ubiquitin protein ligase, is required to degrade another protein, activity-regulated cytoskeletal-associated protein (Arc), which controls synaptic strength or plasticity. If Arc is not degraded, its accumulation weakens synaptic contacts and impairs cognitive and motor functions.
In a series of experiments using the 129-Ube3atm1Alb/J ("AS," 004477) mouse, a model of Angelman syndrome, a research team led by John Marshall, M.D., from Brown University, Providence, R.I., identified specific synaptic signaling factors affected by excess Arc levels. The team found that normalizing Arc expression in this mouse rescues the signaling deficits and may be a promising therapy for people with Angelman syndrome (Cao et al. 2013).
Arc over-expression interferes with BDNF signaling
The AS mouse has abnormally high levels of the Arc protein and has deficits in long-term potentiation (LTP) and learning (Jiang et al. 1998; Bliss and Collingridge 1993). LTP is a long-lasting synapse regulator that is widely thought to facilitate learning and memory (Cooke and Bliss 2006). To appreciate the work of the Marshall team, a basic understanding of several molecules that play key roles in neuronal synapse and LTP is helpful:
- Postsynaptic density protein-95 (PSD-95; Dlg4), a protein that plays a key role in synapse and LTP
- Tyrosine-related kinase B (TrkB; Ntrk2), a receptor that strongly attracts and regulates the activity of several neurotrophins - small protein growth factors that help cells survive and differentiate
- Brain-derived neurotrophic factor (BDNF; Bdnf), one of the neurotrophins that activates TrkB
The Marshall team found that excess Arc in the AS mouse interferes with BDNF signaling by binding to PSD-95 and other synapse effectors, preventing their association with TrkB, an association without which BDNF signaling cannot fully occur. By disrupting the Arc/PSD-95 interaction with CN2097, a novel synthetic compound that binds PSD-95, the Marshall team normalized BDNF signaling and improved LTP induction in the AS mouse.
In summary, the Marshall team's results indicate that, in their AS mouse model, excess Arc due to Ube3A deficiency interferes with TrkB's ability to interact with key factors necessary for BDNF signaling. A compound that disrupts excess Arc binding to PSD-95 may be therapeutic for people with AS.
Models of Angelman Syndrome
- In response to synaptic activity, this model over-expresses Arc, has impaired hippocampal LTP and exhibits learning deficits.
- Heterozygotes are viable and fertile; homozygotes are not as viable, grow slowly, and are uncoordinated.
- Northern blot detects no gene product (mRNA) in homozygous ES cells; in situ hybridization detects no gene expression in hippocampal neurons and Purkinje cells of heterozygotes with a maternal deficiency.
- Due to imprinting, heterozygotes with a maternal deficiency display the phenotype (low motor coordination, impaired LTP, and impaired context-dependent learning), whereas heterozygotes with a paternal deficiency do not.
- Homozygotes and heterozygotes with a maternal deficiency have increased Purkinje cell cytoplasmic levels of transformation related protein 53 (TRP53) and an increased susceptibility to tonic clonic seizures induced by handling.
- This model is heterozygous for the Ube3a targeted mutation.
- Due to imprinting, mice with the maternal deficiency display an Angelman Syndrome phenotype, whereas mice with the paternal deficiency do not.
- In situ hybridization detects no gene expression in hippocampal neurons and Purkinje cells of heterozygotes with a maternal deficiency.
- Maternal transmission of the deficient allele results in a 64-73% reduction in UBE3A protein levels in heart, liver and kidney tissues.
- Mice with the maternal deficiency develop fewer dopaminergic neurons in the substantia nigra and display reduced motor coordination (tremors, ataxia), impaired LTP, defective neocortical plasticity, fluid consumption defects (abnormal licking behavior) and context-dependent learning abnormalities.
- Heterozygotes with a maternal Ube3a deficiency have increased Purkinje cell cytoplasmic levels of transformation related protein 53 (TRP53) and an increased susceptibility to tonic clonic seizures induced by handling.