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Resources » Paper

Moloney AM et al. (2009) European Worm Neurobiology Meeting "The Caenorhabditis elegans orthologue of PICALM, UNC-11, helps protects against Beta-amyloid toxicity"

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  • Comments on Moloney AM et al. (2009) European Worm Neurobiology Meeting "The Caenorhabditis elegans orthologue of PICALM, UNC-11, helps protects against Beta-amyloid toxicity" (0)

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    Status:
    Publication type:
    Meeting_abstract
    WormBase ID:
    WBPaper00035358

    Moloney AM, Fraboulet S, Link CD, Williams J, Lomas DA, Crowther D, & Sattelle DB (2009). The Caenorhabditis elegans orthologue of PICALM, UNC-11, helps protects against Beta-amyloid toxicity presented in European Worm Neurobiology Meeting. Unpublished information; cite only with author permission.

    Authors acknowledge support from MRC and The Alzheimer''s Research Trust. C. elegans has been used in studies of human neurodegenerative diseases (1). Apolioprotein E currently remains the only well confirmed genetic risk factor for sporadic forms of Alzheimer.s disease (AD). However, it is estimated that between 40-70% of AD cases may be caused by genetic variance at additional loci, although much still remains unknown about these. To address this further, this study uses a novel approach to combine an extensive, large-scale, genome-wide association study (GWAS) together with an RNAi screen on a C. elegans transgenic model over-expressing the human amyloid peptide (ABeta1-42) important in AD (2). By applying RNAi approaches to the invertebrate AD model, we can rapidly identify those candidate risk factors which modify Beta-amyloid toxicity and thereby help pinpoint candidate molecular targets and pathways for therapeutic intervention. PICALM (PhosphatidylInositol binding Clathrin Assembly Lymphoid Leukemia Protein) has been identified as an important new AD candidate risk factor (p < 1.92e-08) in the largest GWAS performed to date. The PICALM gene resides on chromosome 11 (p < 1.92e-08) and is essential for clathrin-mediated endocytosis at the synapse. However, very little is known about its precise contribution to synaptic dysfunction in AD. Employing a C. elegans transgenic line CL4176, expressing human ABeta1-42 under a temperature induced system, we have shown that the C.elegans orthologue of PICALM, UNC-11, is necessary to protect against Beta-amyloid toxicity. This application has additionally identified a high frequency of Beta-amyloid modifiers when orthologues of other risk factors, detected in GWAS survey on AD patients, are knocked down using RNAi. Conclusions: This study illustrates the capacity of an invertebrate genetic model of AD to identify novel molecular components or pathways that are implicated in AD pathogenesis as well as prospective targets for therapeutic intervention. References: (1) Culetto E and Sattelle DB. Hum Mol Genet. 2000 9(6):869-77. (2) Link CD., et al., Neurobiol Aging 2003 24(3): 397-413


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