My laboratory is interested in understanding the molecular mechanisms of intracellular movement and the role of transport dysfunction in neurodegenerative diseases. Our focus is on the attachment, function, and regulation of kinesin and dynein microtubule motor proteins. The major questions we are addressing are: 1) What role(s) do these motors play in axonal and dendritic transport, transport of visual system components in photoreceptors, and transport of informational signaling molecules? 2) Does motor-driven transport dysfunction play a major role in neurodegenerative diseases such as retinitis pigmentosum, amyotrophic lateral sclerosis (Lou Gehrigs disease), Huntingtons Disease and Alzheimers disease? 3) How are kinesins and dyneins coupled to intracellular cargoes and regulated? 4) How are appropriate destinations in the neuron found (e.g., axons versus dendrites)? 5) Do intracellular transport processes play important roles in neuronal cell polarization, signaling, growth, and pathfinding? Technologically, our work utilizes molecular and classical genetics, cell biology, and biochemistry in D. melanogaster and M. musculus. Thus, we are making mutants in defined motor proteins and inferring function by phenotypic analysis. We are also using genetic screens to identify novel proteins that couple motors to cargo and regulate their function.
Dr. Lawrence S.B. Goldstein is Professor of Cellular and Molecular Medicine at the University of California, San Diego, School of Medicine. He is also an Investigator with the Howard Hughes Medical Institute. He receives grant funding from the NIH, the Johns Hopkins ALS Center, the Hereditary Disease Foundation, and the Ellison Medical Foundation and has over 100 publications. Dr. Goldstein received his B.A. degree in biology and genetics from UCSD in 1976 and his Ph.D. degree in genetics from the University of Washington, Seattle in 1980. He did postdoctoral research at the University of Colorado at Boulder from 1980-1983 and the Massachusetts Institute of Technology in 1983/1984. He was Assistant, Associate and Full Professor at Harvard University in the Department of Cellular and Developmental Biology from 1984-1993 and moved to UCSD and HHMI in 1993. His awards include a Senior Scholar Award from the Ellison Medical Foundation, an American Cancer Society Faculty Research Award, and the Loeb Chair in Natural Sciences when he was at Harvard University. His research is focused on understanding the molecular mechanisms of intracellular movement in neurons and the role of transport dysfunction in neurodegenerative diseases. His lab provided the first molecular descriptions of kinesin structure and organization, and has recently discovered important links between transport processes and diseases such as Alzheimers Disease and Huntingtons Disease. Dr. Goldstein has also had an active role in National Science policy. He has served on many public science advisory committees, has written about, spoken about, and been interviewed on numerous occasions on science issues by print and broadcast media, and has testified on a number of occasions in the U.S. House of Representatives and the Senate about NIH funding and stem cell research. As a cofounder and consultant of the biotechnology company Cytokinetics he has also had an active role in private industry.
Marszalek, J.R., Liu, X., Roberts, E.A., Chui, D., Marth, J., Williams, D.S., and L.S. B. Goldstein. (2000). Genetic Evidence for a Kinesin-II Mediated Pathway for Opsin Transport in Mammalian Photoreceptors. Cell 102: 175-187.
Bowman, A.B., Kamal, A., Philp, A.V., Ritchings, B.W., McGrail, M., Gindhart, J. G., and L.S.B. Goldstein. (2000). Kinesin Dependent Axonal Transport is Mediated by the Sunday Driver (SYD) Protein. Cell 103: 583–594.
Kamal, A., Stokin, G.B., Yang, Z., Xia, C.H., and L.S.B. Goldstein. (2000). Axonal transport of amyloid precursor protein requires formation of a complex with kinesin-I. Neuron 28: 449-459.
Sosa, H., Peterman, E.J.G., Moerner, W.E., and L.S.B. Goldstein. (2001). ADP-induced rocking of the kinesin motor domain revealed by single-molecule fluorescence polarization microscopy. Nature Structural Biology 8: 540-544.
Gunawardena, S. and L.S.B. Goldstein. (2001). Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32: 389-401.
Kamal, A, Almenar-Queralt, A., LeBlanc, J.F., Roberts, E.A., and L.S.B. Goldstein. (2001). Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 414: 643-648
Xia, C.H., Roberts, E.A., Her, L.S., Liu, X, Williams, D.S. Cleveland, D.W. and L.S.B. Goldstein. (2003). Abnormal Neurofilament Transport Caused by Targeted Disruption of Neuronal Kinesin Heavy Chain KIF5A. J. Cell Biol. 14:55-66
Gunawardena, S., Her, L.S., Brusch, R.G., Laymon, R.A., Niesman, I.R., Gordesky-Gold, B., Sintasath, L., Bonini, N.M., and L. S. B. Goldstein. (2003). Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40: 25-40.
Clement, A.M., Nguyen, M.D., Roberts, E.A., Garcia, M.L., Boillee, S., Rule, M., McMahon, A.P., Doucette, W., Siwek, D., Ferrante, R.J., Brown, R.H., Jr., Julien, J.-P., Goldstein, L.S.B., and D.W. Cleveland. (2003). Wildtype non-neuronal cells extend survival of SOD1 mutant motor neurons in an ALS mouse model. Science 302: 113-117.
Goldstein, L.S.B. (2003). Do disorders of movement cause movement disorders and dementia? Neuron 40: 415-425.