Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model

Written by Richard Newton; edits by Rebecca Burdine, Ph.D.

Angelman Syndrome (AS) is caused by loss of functional UBE3A protein expression from the maternal chromosome in affected individuals, but the specific roles this protein plays in the human brain are still being discovered.

The UBE3A protein functions as an ubiquitin ligase, adding ubiquitin to specific protein targets which typically marks them for destruction. Since ubiquitin ligases are involved in the break down and clean-up of proteins that have reached the end of their usefulness, they are sometimes referred to as “housekeeping proteins.” Housekeeping proteins are those involved in the routine maintenance of basic cell function and are thought to be expressed at fairly constant levels in different conditions (1). However, research is showing that there is more going on with how and why the UBE3A gene is expressed than is expected of a housekeeping gene.

Recent research conducted by Dr. Weeber and his team (2), funded by FAST, is shedding more light on the expression of the Ube3A gene in mouse – the triggers that cause the gene to create its protein. In their paper, Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model, Dr. Weeber and his team show that not only did they observe that neuronal activity could regulate expression of maternal Ube3a, they observed changes in the amount of paternal Ube3a expression as well.

Most of what we have learned about the expression of Ube3a protein was determined while the system was at rest. That is not to say it was static, because biological systems rarely are, but the neurons weren’t being stimulated by excitatory or inhibitory input – they were essentially “resting”. A recent paper by Greer in 2010 demonstrated that Ube3a expression was upregulated during induced seizures or in response to new environments, suggesting a link between neuronal activity and Ube3a expression (3). This current report extends those findings and demonstrates that “learning events” increase Ube3a protein levels. Intriguingly, the increase in Ube3a protein came from expression of both the maternal and paternal genes in the hippocampus. Thus, the notion that the paternal gene is “silent,” or not expressed, in the brain is beginning to be challenged.

Additionally, the research showed that lack of Ube3a protein prevented activation of other proteins, specifically the ERK (Extracellular-signal-Regulated Kinases)1/2 kinase proteins. ERK 1/2 kinases control expression of other genes and are activated by addition of a chemical phosphate (referred to as “phosphorylation“). The reduction of phosphorylated ERK in mice lacking maternal Ube3a is significant as ERK activity is well known to be necessary for synaptic plasticity and formation of  memories. Thus, this may be a mechanism that contributes to reported deficits in synaptic plasticity and cognitive function in AS mice and in patients with AS.

Taken together, the findings provide new insight into both the expression of Ube3a by neuronal activity and also Ube3a’s potential role in synaptic plasticity. In the future, targets of ERK1/2 can be explored to identify potential “druggable” targets to explore for AS therapeutics. The findings also highlight the need to explore the mechanisms that control expression from the paternal chromosome. These may reveal additional ways we can utilize to increase the levels of UBE3A in individuals with AS, but should also be taken into account with current efforts to reactivate the paternal allele.

To read the abstract on PubMed, click here.

1. Human housekeeping genes, revisited. Eisenberg E, Levanon EY. Trends Genet. 2013 Oct;29(10):569-74. PMID:23810203

2. Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model. Filonova I, Trotter JH, Banko JL, Weeber EJ. Learn Mem. 2014 Jan 16;21(2):98-104. PMID: 24434871

3. The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim TK, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME. Cell. 2010 Mar 5;140(5):704-16. PMID: 20211139