Return to Emory Report home pageSimilarities between a gene in a millimeter-long species of worm and a gene on chromosome 14 in humans that is mutant in people who suffer from the most aggressive form of Alzheimer's Disease may have major implications for future research on the disease.
Headlines around the country during the last week of June featured researchers from the University of Toronto who discovered a gene identified as s182 that, when mutated, causes early-onset familial Alzheimer's disease. The researchers reported results of their work in the June 29 issue of Nature.
That article discusses the similiarities of the human gene and a gene found in the worm species Caenorhabditis elegans, that was cloned and sequenced by Emory researcher Steve L'Hernault and graduate student Michele Arduengo.
"The only published (DNA) sequence that has any homology with s182 is the spe-4 gene, which was cloned and sequenced in our lab," said L'Hernault, associate professor of biology. Homology refers to genes that share a common ancestor.
L'Hernault has been researching spermatogenesis (how sperm are made) in C. elegans for the last 11 years; Arduengo has been collaborating in that research for the last six years. Some people consider this type of research to be esoteric and "curiosity driven." However this newly-discovered connection with Alzheimer's research sheds a different light on their work. According to L'Hernault, spe-4 offers scientists a valuable research tool that complements those available to human geneticists.
The next step in research on s182 is to determine the gene's normal function, and that's where spe-4 and C. elegans could play a useful role. "In order to study in a detailed fashion how the molecule works, you need to be able to create mutations at will," said L'Hernault. "You can't put a mutated gene back into a human, but you can do that with worms. We have at our disposal a strategy to get at what this gene does in ways that for ethical and practical reasons can't be explored in humans."
The gene spe-4 was originally identified by L'Hernault and Arduengo as causing sterility in worms when it is disrupted. L'Hernault's research focuses on two major problems: cellular differentiation, or how a cell assumes specialized form and function, and sperm function -- how genes and genetic mutations affect fertilization.
C. elegans, according to the two researchers, is the ideal system in which to perform classical genetic research, which involves following patterns of inheritance. They cite five attributes that make C. elegans so ideal: a short generation time; rapid growth cycle; a large brood of offspring; ease of manipulation; and low cost. "It's cheap to work with," said L'Hernault, "and results come fairly quickly." He added that the unusual reproductive biology of C. elegans makes it one of the best systems for studying spermatogenesis.
L'Hernault and Arduen-go's research on spe-4 involves using the electron microscope to figure out what is defective in the sperm cells where spe-4 is disrupted. The discovery that one of the cells' membranes is defective is "an enormous clue in Alzheimer's research," explained L'Hernault.
The connection between worm sperm and human genes may sound absurd, and L'Hernault and Arduengo admit that absurdity. There are more attributes of C. elegans sperm that make the connection even more ridiculous than it initially seems, such as the fact that C. elegans sperm are crawling sperm. The sperm of most species swim using an appendage called a flagellum. C. elegans sperm have no flagellum, so they must crawl in order to find and fertilize an egg.
"The connection with Alzheimer's literally dropped out of the sky," said L'Hernault. "It's the scientific equivalent of winning the lottery. What was once considered esoteric becomes especially relevant."
L'Hernault takes the opportunity to put a plug in for basic science research. The research that originally began as identifying a gene necessary for sperm production in worms may have impact in understanding a devastating disease. "Basic research has a whole lot more to offer in terms of clinical relevance than many people think," said L'Hernault. "You have to support excellent science; some fraction of that is going to have an impact. It's hard for people to accept that, particularly since we live in a society of instant gratification."
L'Hernault has set up a collaboration with Allan Levey, associate professor of neurology, to pursue the connection between spe-4 and Alzheimer's Disease.
-- Nancy M. Spitler
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