Voor het Angelman Syndroom

Drosophila homologue of AS ubiquitin ligase regulates the formation of terminal dendritic branches

Just like the paper by Wu and colleagues earlier this year (1), this study describes the generation and phenotype (= appearance) of a fruit fly, which lacks the Ube3a gene (called Dube3a from Drosophila-Ube3a). Since lack of the Ube3a gene causes AS, this fly could be a good model for the disease.
This paper focuses on the way the neurons look (neuronal morphology) in the AS fly mutant. The authors found reduced development of the neurons (less branches) when Dube3a was absent. Interestingly, they also found reduced neuronal branches when Dube3a levels were higher than normal. Moreover the author’s showed that too much Dube3a killed the flies at the larval stages.

This is an interesting paper that confirms the previous drosophila findings (1) that too much Dube3a is not healthy for cells and disrupts normal development. These findings also emphasize that the imprinting of the Ube3a gene (=silencing the chromosomal copy obtained from the father) is there for a good reason; having Ube3a made from both the fathers and mothers copy would probably affect the development of the child. This has important therapeutic consequences: development of a therapy that would reintroduce Ube3a in the brain cells might be deleterious if the levels of Ube3a became higher than normal!

What is the relevance of the finding that loss of Dube3a causes a reduction neuronal branching? This is less clear. A detailed analysis of a mouse model of AS, has not shown such differences in neuronal branching (2). Hence the importance of this finding for the disease is questionable. Potentially the fly is more sensitive to changes in Dube3a levels than mice. Because autopsies of human AS brains are extremely rare we don’t know what the neurons look like in AS patients, but it is likely that it would be more similar to the mouse findings than to the fly findings.

(1) Wu et al. A Drosophila model for Angelman syndrome. Proc Natl Acad Sci USA (2008) vol. 105 (34) pp. 12399-404

(2) Dindot et al. The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet (2008) vol. 17 (1) pp. 111-8

Topic: Animal models
Title: The Drosophila homologue of the Angelman syndrome ubiquitin ligase regulates the formation of terminal dendritic branches
Authors: Lu Y, Wang F, Li Y, Ferris J, Lee JA, Gao FB
Journal: Hum Mol Genet (2009) vol. 18 (3) pp. 454-62
(Contributed by Ype Elgersma, Erasmus MC, Rotterdam, The Netherlands)

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