Editor’s note: Science Scan is a roundup of recently published biotechnology-relevant research.
A new and offbeat risk factor for Alzheimer’s disease (AD) has surfaced. So far, the key factors presaging the dementia are advanced age and high apolipoprotein enzyme 4 (APOE4). Now a paper in Science, dated Feb. 1, 2002, proposes another hypothetical AD risk: bacterial infection.
The article is titled: “Role of Escherichia coli curli operons in directing amyloid fiber formation.” Its senior author, molecular microbiologist Scott Hultgren, and lead author, Matthew Chapman, are at Washington University in St. Louis. Another co-author, Staffan Normark, at the Karolinska Institute in Stockholm, Sweden, is responsible for coining the term “curli” to describe the curly appearing amyloid fibers spun by the E. coli microbe, as well as by Salmonella species.
“What we report in this paper,” Hultgren told BioWorld Today, “is that these bacterial fibers produced by E. coli are biochemically and structurally identical to amyloid fibers, which are the hallmark of many diseases prominently including Alzheimer’s. That was a very exciting result in itself. To take it one step further, we started to develop this bacterial function as a model system for studying amyloid formation. The current thinking,” he continued, “is that amyloid tends to form through a protein misfolding pathway. Amyloid formation is generally thought to be a biological mistake. Within the E. coli system, we think it’s very different. We propose that E. coli is doing this on purpose. That prokaryotic microbe has figured out how to build an amyloid fiber.
“Until now,” Hultgren pointed out, “there haven’t been any bacterial fibers shown to be amyloid, which is considered a eukaryotic fiber. Secondly, this is a directed and purposeful process that bacterium is doing it to serve some function. One of the things we’re greatly interested in is the molecular basis of how fibers are formed in general. Through those basic studies we’ve uncovered some fundamental underlying mechanisms that may explain fiber stability. This, of course, leads to interesting ideas about broad-spectrum therapeutics.
“The finding also raises the important question,” Hultgren observed, “of whether bacterial infections play some role in amyloid diseases, including AD. The human disorders,” he pointed out, “also are thought to involve dissolved amyloid proteins that undergo a change in shape and aggregate into fibers. When these fibers develop in the brain, specifically in senile amyloid plaques, that leads to Alzheimer’s disease.”
Hultgren went on: “Once we understand the details of how these bacterial proteins are assembled into amyloid-like fibers, then we can begin to try to rationally develop compounds that could inhibit or dissociate those fibers perhaps a small-molecule substance like a pill. Furthermore,” he concluded, “this work raises the open question of whether certain neurodegenerative disorders that are caused by amyloids could be linked to any infectious diseases something never fully appreciated before.”
Surprise Disclosure Fingers Glycine, Not Glutamate, As Top Actor in Revving Brain
Glutamate best known as MSG (monosodium glutamate) is reputedly the most important excitatory neurotransmitter in the brain. Its receptors are the focus of intense research, as a fine line exists between the degree of stimulation required for normal nerve cell behavior and nerve cell death, caused by overstimulation of the edgy glutamate receptors. This occurs in head and spinal cord injury, stroke, epilepsy, Alzheimer’s and Huntington’s diseases, amyotrophic lateral sclerosis, AIDS dementia and other cerebral disorders.
A paper in Nature dated Jan. 30, 2002, reports cloning of the seventh and final subunit of the glutamate receptor family. Its title: “Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.” The article discloses the surprising discovery that receptors containing the new subunit are activated not by glutamate but by glycine the simplest essential amino acid which is a quite different brain chemical. The surprise inheres in the fact that until now glycine was thought to damp down the nervous system rather than rev it up. This new finding is expected to provide unexpected insights into certain brain diseases associated with excitotoxicity or overstimulation of these receptors.
The Nature paper’s senior author is clinical and research neurologist Stuart Lipton, director of the Burnham Institute’s Del E. Webb Center for Neuroscience and Aging in La Jolla, Calif. “What may shake up all of our thinking about neurodegenerative diseases associated with excitotoxicity,” he stated in a press release, “is that these disorders may in fact be mediated in part by glycine rather than by glutamate.”
Japanese Researchers Use Gene Therapy To Reverse Effects Of Insufficient Sperm In Infertile Male Mice
About one in three cases of infertility can be laid at the door of the male. This sometimes results from a genetic defect in Sertoli cells of the testes, which coach developing sperm to mature properly. Japanese pathologists enlisted gene therapy to treat mice made infertile by defective Sertoli cells. They injected a normal copy of the mutant gene, delivered by an adenoviral vector, into the murine testes. This strategy restored the animals’ ability to make mature sperm, but in much smaller numbers than produced by normal mice.
Then, taking a page from human in vitro fertilization techniques, the researchers implanted the scanty but healthy sperm from their gene-treated animals into female surrogate mother mice. Their embryos developed into healthy, fertile offspring.
A paper in the Proceedings of the National Academy of Sciences (PNAS), dated Feb. 5, 2002, reports this experiment under the title: “Adenovirus-mediated gene delivery and in vitro microinsemination produce offspring from infertile male mice.” Its authors are at Kyoto University. They suggest that this technique offers a promising treatment possibility for male infertility resulting from other genetic defects, and for which no effective therapy yet exists.