Clayton Foundation Laboratories for Peptide Biology
Helen McLoraine Chair in Molecular Neurobiology
Kuo-Fen Lee, a professor in the Clayton Foundation Laboratories for Peptide Biology, studies the genes and molecules that guide brain cell development. He has considerable expertise in producing mice to study the effects of specific genes on nervous system function. His lab focuses on how disruptions in development and maintenance of nerve cells and their supporting cells can contribute to neurodegenerative diseases, such as Alzheimer's disease, neuroendocrine diseases, such as anxiety, and neuromuscular diseases.
Lee and his lab use gene "knock-out" technology to delete or alter the genes of mice models to observe the physiological effects. This may speed up by decades the discovery of how abnormalities occur in how brain cells communicate with each other. The ultimate goal of this work is to develop therapies to prevent brain cell death and treat disorders.
Proteins, like people, are often judged by the company they keep. A protein known as p75, for instance, belongs to the same family as tumor necrosis factor, a protein that can induce cell death. Thus, in addition to regulating neuronal growth, survival and degeneration and guiding nerve fibers in growing embryos to their final destinations, p75 was widely thought to mediate cell death in some context.
Various in vitro studies have examined p75 in combination with beta amyloid, seeking evidence that it helps induce nerve cell death in Alzheimer's disease. A team of scientists in Lee's laboratory, however, found that p75 instead has a neuroprotective effect on the sympathetic nervous system.
Scientific interest in the peripheral nervous system has been growing as investigators studying neurodegenerative diseases seek new insights into disease progression. To gather evidence about p75 and the sympathetic nervous system, Lee's group crossed a mouse model for Alzheimer's disease with a line of mice genetically modified to lack the gene for p75. Without p75, they theorized, the neurotoxic effects of beta amyloid would be reduced, and the mice would show fewer Alzheimer's symptoms.
Along with profound motor problems, the p75-deficient mice exhibited severe defects in the wiring of nerves to multiple organs, and the majority died within just three weeks. (Mice normally live up to two years.) But when the researchers scaled down the production of toxic beta amyloid by deleting one copy of BACE1, which encodes the molecular shears that make the first cut in the production of beta amyloid fragments, the nerves in the sympathetic nervous system of p75-deficient mice were substantially restored.
This was the first time the interplay between p75 and beta amyloid in the peripheral sympathetic system has been demonstrated. Lee's findings not only challenge the prevailing view of p75's harmful role in Alzheimer's, but could lead to new insights and, ultimately, new protocols for managing the secondary deficits that accompany the condition's hallmark dementia and memory loss.