Science at the Jack Miller Center - Research

Brian Popko, Ph.D.

Research Profile

My laboratory takes a molecular genetic approach to obtain a better understanding of the normal function, as well as dysfunction, of the nervous system. Over the past decade, as the DNA sequence of the human and mouse genomes has become known, the techniques associated with the identification and isolation of mutant genes in the mammalian genome have been dramatically improved. Furthermore, remarkable advances have been made in the development of quantitative approaches toward the molecular analysis of complex biological systems. Moreover, our ability to manipulate the mouse genome has become increasingly sophisticated, such that intricate mouse models can be generated. The research interest of my laboratory exploits these recent advances and includes three general areas of inquiry.

1. Mouse models: The detailed analyses of spontaneous mouse mutants, as well as the generation of transgenic models of disease, have proven to be extremely valuable tools in understanding of human disorders. These efforts have resulted in the identification of genes responsible for human genetic disorders, and the generation of authentic models of human diseases. Additionally, the "phenocopying" of particular traits of a syndrome have proven to be very useful. Mouse models of Alzheimer's disease, Creutzfeldt-Jakob disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis have all proven extremely informative in our current understanding of these disorders, as well as in the design of therapeutic approaches. Our laboratory is focusing considerable effort on the generation and analysis of mouse models of peripheral neuropathies with the expectation that they will provide similar benefit.

2. Molecular profiling: Microarray techniques have been developed over the past few years that allow for the simultaneous monitoring of the expression of tens of thousands of genes in a particular tissue or cell. These approaches are useful in uncovering the molecular causes and consequences of human disorders. We are exploiting microarray technology to examine the molecular profile displayed by various peripheral neuropathies. By comparing these data with similar analyses of the mouse models generated above, we should be able to begin to distinguish disease causing events from the effects of these disorders at the molecular level.

3. Human genetics: Knowing the DNA sequencing of the human genome has facilitated efforts to identify genetic loci responsible for human disease. In addition to providing a molecular explanation for a particular genetic disorder, these approaches also provide fundamental information concerning disease processes in the respective tissue. Although the majority of peripheral neuropathies might not have a primary genetic cause, the molecular characterization of genetic disorders that display PNS abnormalities will likely provide general insight into these diseases. An effort to identify families perhaps consanguineous ones, as has recently been done with other neurological disorders, that display genetic peripheral neuropathies has been initiated.

Selected Publications (comprehensive list):

Marcus, J., Dupree J.L. and Popko B. (2002) Myelin-Associated Glycoprotein and Myelin Galactolipids Stabilize Developing Axo-Glial Interactions. Journal of Cell Biology 156:567-577.

Gao X., Gillig T.A., Ye P., D'Ercole A.J., Matsushima G.K., Popko B. (2000) Interferon-gamma protects against cuprizone-induced demyelination. Molecular and Cellular Neuroscience 16:338-349.

Popko B. (ed): Mouse Models in the Study of Genetic Neurological Disorders, Plenum Publishing Co, New York, 1999.

Dupree, J.L., Girault, J.-A., Popko B. (1999) Axo-glial interactions regulate the localization of axonal paranodal proteins. Journal of Cell Biology 147:145-152.

Fujita N., Kemper A., Dupree J., Nakayasu H., Maeda N., Suzuki K., Suzuki K., Popko B: (1998) The cytoplasmic domain of the large myelin-associated glycoprotein isoform is needed for proper CNS but not PNS myelination. Journal of Neuroscience 18:1970-1978.

Dupree J., Coetzee T., Blight A., Suzuki K., Popko B: (1998) Myelin galactolipids are essential for proper node of Ranvier formation in the CNS. Journal of Neuroscience 18:1642-1649.

Coetzee T., Suzuki K., Popko B. (1998) New perspectives on the function of myelin galactolipids. Trends in Neurosciences 21:126-130.

Coetzee T., Fujita N., Dupree J., Shi R., Blight A., Suzuki K., Suzuki K., Popko B. (1996) Myelination in the absence of galactocerebroside and sulfatide: Normal structure with abnormal function and regional instability. Cell 86:209-219.

Rath E.M., Kelly D., Bouldin T.W., Popko B. (1995) Impaired peripheral nerve regeneration in a mutant strain of mice (Enr) with a Schwann cell defect. Journal of Neuroscience 15:7226-7237.