Temperature-Dependent Lethality of APL-1, a C. elegans Protein Related to Human A

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DESCRIPTION (provided by applicant): Deposition of dense plaques and the presence of neurofibrillary tangles are two postmortem criteria used in the definitive diagnosis of Alzheimer's disease. The major component of the dense plaques is a 40 amino acid beta-amyloid peptide that is derived from the larger amyloid precursor protein (APP). Two alternative pathways have been suggested in the processing of APP, only one of which produces the beta-amyloid peptide. The function of APP and the pathways in which APP acts are still poorly understood. A family of APP-related proteins is present in mammals. Knockout of the APP family in mice leads to postnatal lethality and type II lissencephaly, indicating that the APP family has essential functions during development. We are interested in studying the function of APP and are approaching this problem by examining an APP-related gene in a simple model system, the nematode Caenorhabditis elegans. C. elegans has the experimental advantages of being easy to manipulate genetically and being able to generate transgenic animals quickly. We have identified a C. elegans gene, apl-1, that encodes an APP- related protein. APL-1 has strong sequence homology with the APP family proteins. Knockout of apl-1 leads to larval lethality, which can be rescued by germline transformation of a apl-1 genomic fragment. Interestingly, the apl-1 lethality can also be rescued by transformation with constructs encoding only the extracellular domain of APL-1. High levels of APL-1 overexpression lead to an incompletely penetrant larval lethality, suggesting that levels of APL-1 must be tightly regulated. Animals carrying the apl-1(yn5) mutation are viable and produce high levels of only the APL-1 extracellular domain. Recently, we found that raising apl-1(yn5) mutants at slightly elevated temperatures induces lethality. We propose to: 1) characterize APL-1 signaling and determine the basis of the apl-1(yn5) lethality; and 2) identify genes that act in the apl-1 pathway. C. elegans provides a tractable genetic model in which many approaches not feasible for use in mammalian systems can be used to understand APL-1 function and identify pathways in which APL-1 acts. Understanding the pathways through which APL-1 functions may give insights into the function and regulation of APP in higher animals, such as man.