. A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS One. 2008;3(6):e2334. PubMed.

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  1. The identification of a gene mutation associated with a human disease can pave the way for the generation of genetically modified animals as experimental models of the human condition. Three papers in the last six months have reported how Drosophila may be used to model the human motor neuron disease ALS8, by the expression of the mutated human VAPB gene or the homologous Drosophila protein (1-3). An earlier report from Chai et.al. demonstrated that both the human wild-type and ALS8 mutant forms of VAPB could rescue the phenotype of dVAP-deficient flies (1). Ratnaparkhi et. al. have now reported that the mutant form of the Drosophila protein is unable to rescue a VAPB deficiency as fully as the wild-type protein and, moreover, can suppress the activity of the wild-type protein. This interesting property is also well demonstrated with a thoracic bristle phenotype assay. Both groups employed the GAL4/UAS system to express wild-type and ALS8 mutant forms of dVAP in different tissues. One obvious potential cause for the differences seen is that the expression levels of the respective proteins are different. Neither paper presents any quantitative data, and in the supplementary material provided by Ratnaparkhi et al., the single immunoblot indicates a very modest level of overexpression in just a single genotype. In addition, the human protein and Drosophila mutant proteins may not be fully functionally equivalent. Currently, most evidence seems to support the hypothesis that the ALS8 mutation has reduced activity and acts in a dominant-negative fashion. However, in addition to the evidence provided by Chai et al., there is some indication that the vertebrate VAPBP56S may also exhibit a gain of function. Thus, elevating levels of wild-type VAPB can inhibit transcription regulated by ATF6, whereas the mutant VAPBP56S has a greater inhibitory affect. In contrast, reduction of VAPB levels enhances AT6 dependent transcription (4).

    The genetic link between dVAP and the BMP signaling system is extremely interesting, and clearly supported by the data. However, since VAP proteins in other systems have been shown to influence membrane trafficking, it will be important to determine the specificity of any VAP-mediated effect on membrane associated signaling systems(5-7). Also, some of the experiments rely on quantitative fluorescence microscopy that is technically very demanding, and is most compelling when done relative to a co-stained control signal rather than between samples.

    The reports from these groups are very significant since they clearly demonstrate the fact that phenotypes associated with the ALS8 mutation can be studied in Drosophila. The elegant and powerful genetic tools available in this organism can now be used to examine the molecular details of motor neuron degeneration and to screen for potential therapeutic compounds.

    References:

    . hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction. Hum Mol Genet. 2008 Jan 15;17(2):266-80. PubMed.

    . A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS One. 2008;3(6):e2334. PubMed.

    . The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell. 2008 Jun 13;133(6):963-77. PubMed.

    . VAPB interacts with and modulates the activity of ATF6. Hum Mol Genet. 2008 Jun 1;17(11):1517-26. PubMed.

    . A functional role for VAP-33 in insulin-stimulated GLUT4 traffic. Traffic. 2000 Jun;1(6):512-21. PubMed.

    . A VAMP-binding protein from Aplysia required for neurotransmitter release. Science. 1995 Sep 15;269(5230):1580-3. PubMed.

    . ERG30, a VAP-33-related protein, functions in protein transport mediated by COPI vesicles. J Cell Biol. 1999 Jul 26;146(2):301-11. PubMed.

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