A Drosophila model for Angelman syndrome

Wu, Y., Bolduc, F. V., Bell, K. G., Tully, T., Fang, Y., Sehgal, A., Fischer, J. A. (August 2008) A Drosophila model for Angelman syndrome. Proc Natl Acad Sci U S A, 105 (34). pp. 12399-404.

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URL: http://www.ncbi.nlm.nih.gov/pubmed/18701717
DOI: 10.1073/pnas.0805291105


Angelman syndrome is a neurological disorder whose symptoms include severe mental retardation, loss of motor coordination, and sleep disturbances. The disease is caused by a loss of function of UBE3A, which encodes a HECT-domain ubiquitin ligase. Here, we generate a Drosophila model for the disease. The results of several experiments show that the functions of human UBE3A and its fly counterpart, dube3a, are similar. First, expression of Dube3a is enriched in the Drosophila nervous system, including mushroom bodies, the seat of learning and memory. Second, we have generated dube3a null mutants, and they appear normal externally, but display abnormal locomotive behavior and circadian rhythms, and defective long-term memory. Third, flies that overexpress Dube3a in the nervous system also display locomotion defects, dependent on the ubiquitin ligase activity. Finally, missense mutations in UBE3A alleles of Angelman syndrome patients alter amino acid residues conserved in the fly protein, and when introduced into dube3a, behave as loss-of-function mutations. The simplest model for Angelman syndrome is that in the absence of UBE3A, particular substrates fail to be ubiquitinated and proteasomally degraded, accumulate in the brain, and interfere with brain function. We have generated flies useful for genetic screens to identify Dube3a substrates. These flies overexpress Dube3a in the eye or wing and display morphological abnormalities, dependent on the critical catalytic cysteine. We conclude that dube3a mutants are a valid model for Angelman syndrome, with great potential for identifying the elusive UBE3A substrates relevant to the disease.

Item Type: Paper
Subjects: diseases & disorders
organism description > animal > insect > Drosophila
diseases & disorders > mental disorders > sleep disorders
organism description > animal > insect
diseases & disorders > congenital hereditary genetic diseases > mental retardation
CSHL Authors:
Communities: CSHL labs > Tully lab
School of Biological Sciences > Publications
Depositing User: Matt Covey
Date: 26 August 2008
Date Deposited: 26 Feb 2013 21:44
Last Modified: 08 Nov 2017 21:30
PMCID: PMC2527923
Related URLs:
URI: https://repository.cshl.edu/id/eprint/27517

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