This study builds directly on two earlier studies: First, Edwin Weeber (at that time a postdoc in the lab of David Sweatt) and his colleagues found that the activity of calcium/calmodulin-dependent kinase Type 2 (CaMKII) (an essential enzyme for neuronal function) was decreased by approximately 30% in the Ube3a mutant mice, even though the amount of CaMKII enzyme was unaffected (1) .
In parallel, Ype Elgersma (at that time a postdoc in Alcino Silva?s lab) showed that CaMKII can inhibit itself by a modification reaction (called autophosphorylation) which occurs at a specific place within the enzyme (designated as Thr305 and Thr306). Furthermore he showed an increased amount of inhibited CaMKII, resulted in a severe learning deficits (2) .
Edwin Weeber and Ype Elgersma exchanged these findings and decided to investigate whether the increased amount of inhibited CaMKII in the Ube3a mutant was indeed causing the neurological problems in the Ube3a mutants. They did this by crossing the Ube3A mutant (from the Beaudet laboratory) with a CaMKII mutant made by Ype Elgersma, which could not be inhibited anymore. The obtained double mutants were analyzed at both laboratories.
Both in the Elgersma lab, as well as in the Weeber lab, it was found that the Ube3a/?CaMKII double mutants showed a decreased amount of inhibited CaMKII, and nearly restored levels of CaMKII enzymatic activity. More importantly, they showed that the learning and motor deficits were completely rescued, and plasticity as measured in brain slices was back to normal. Another important feature of the disease, epilepsy, was still present in some of the double mutants, but the number of animals showing epilepsy was threefold reduced as compared with the Ube3a single mutants. Finally, it was noted that the moderate (but significant) increase in bodyweight of the Ube3a mice was rescued. Although overweight is not known as a characteristic feature of the disease, overweight is observed in the majority (85%) of AS children carrying the UBE3A mutation. Thus, even in that respect the Ube3a mouse turned out to be a good model, and the absence of increased bodyweight in the double mutants indicated that increased self-inhibition of CaMKII was also responsible for this aspect of the disease.
Implication and future direction.
Knowing that the increased inhibition of CaMKII is responsible for the major neurological hallmarks, is an important step to understand the mechanisms underlying this severe neurological disorder. Future studies should focus on the link between the absence of Ube3a and the increased self-blocking of CaMKII. Hopefully this knowledge will lead to the development of therapies.
Authors: Van Woerden GM, Harris KD, Hojjati MR, Gustin RM, Qiu S, de Avila Freire R, Jiang YH, Elgersma Y, Weeber EJ
Journal: Nature Neuroscience 2007, 10 :280-282.
References
1. E. J. Weeber et al., J Neurosci23, 2634 (2003).
2. Y. Elgersma et al., Neuron36, 493 (2002).
About the first author:
Geeske van Woerden was born in 1980 in Utrecht, the Netherlands. She studied Medicine at the Erasmus MC University Medical Center in Rotterdam, after which she started her PhD in the lab of Dr. Ype Elgersma at the same institute. The lab of Dr. Ype Elgersma is interested in the molecular mechanisms underlying memory formation and cognitive disorders.
Geeske van Woerden is in involved in CaMKII research (linked to Angelman Syndrome), as well as work on Neurofibromatosis (NF1). For more information go to (Research-Elgersma).
Corresponding address
For more information on this paper contact Geeske van Woerden or Ype Elgersma:
Dept. of Neuroscience, Erasmus MC
Dr. Molewaterplein 50
3015 GE Rotterdam
The Netherlands
(Research-Elgersma)
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