Functional Screening of Alzheimer Pathology Genome-wide Association Signals in Drosophila

Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2011; 88(2):232-8. DOI: 10.1016/j.ajhg.2011.01.006
Source: PubMed


We have leveraged a Drosophila model relevant to Alzheimer disease (AD) for functional screening of findings from a genome-wide scan for loci associated with a quantitative measure of AD pathology in humans. In six of the 15 genomic regions evaluated, we successfully identified a causal gene for the association, on the basis of in vivo interactions with the neurotoxicity of Tau, which forms neurofibrillary tangles in AD. Among the top results, rs10845990 within SLC2A14, encoding a glucose transporter, showed evidence of replication for association with AD pathology, and gain and loss of function in glut1, the Drosophila ortholog, was associated with suppression and enhancement of Tau toxicity, respectively. Our strategy of coupling genome-wide association in humans with functional screening in a model organism is likely to be a powerful approach for gene discovery in AD and other complex genetic disorders.

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Available from: David Bennett, Dec 11, 2014
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    • "In this regard, SPTBN4 also anchors CAMKII to the axon initial segment (Hund et al., 2010), and, thus, CAMKII mislocalization upon SPTBN4 epigenetic loss could cause tau hyperphosphorylation, a common finding in Alzheimer's disease (Xiao et al., 1996). Supporting this hypothesis, RNA interference of the SPTBN4 orthologue in a Drosophila Alzheimer's disease model also enhances tau toxicity (Shulman et al., 2011). "
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    Brain 09/2013; 136(10). DOI:10.1093/brain/awt237 · 9.20 Impact Factor
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    • "In humans, impaired glucose transport across the blood-brain barrier due to GLUT-1 mutations causes the glucose transporter protein syndrome, which is characterized by infantile seizures, developmental delay, and microcephaly (Klepper et al., 1999). GLUT-1 mutations have also been linked to learning disability and Alzheimer's disease (Guo et al., 2005; Shulman et al., 2011). In ECs of intact coronary arteries, glucose is taken up at the periphery of the cell and accumulates close to cell-tocell junctions, where the majority of glucose transporters are anchored. "
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    Cell metabolism 08/2013; 18(5). DOI:10.1016/j.cmet.2013.08.001 · 17.57 Impact Factor
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    • "Off-the-shelf genetic tools in Drosophila, including mutations and inducible RNA interference (RNAi), allow the functions of specific genes to be rapidly queried; a Drosophila genetic approach has recently been used to follow up a small-scale GWAS for Alzheimer pathology [11]. Here we make use of the advantages of Drosophila as a model system for exploration of whole-animal metabolism. "
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    ABSTRACT: Background Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits. Results Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity. Conclusion Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.
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