The primary goals in the Goldstein lab are to unravel how molecular motors interact with, and control the behavior of, axonal vesicles, and to relate this understanding to the molecular basis of neuronal defects in Alzheimer's Disease (AD) and Niemann Pick type C disease.
We are taking advantage of pluripotent stem cell lines that contain known mutations that cause hereditary Alzheimer's disease, as well as Niemann Pick Type C disease. This latter disease is of interest because it directly ties cholesterol trafficking and transport to what appears to be a pediatric form of Alzheimer type dementia.
We are also using these cell lines and animal models to probe basic mechanisms of vesicle movement and sorting in neurons, and how such mechanisms inter-relate with disease development. In a related endeavor, we are probing how genetic variation predisposes to different neuronal phenotypes and disease by developing pluripotent stem cell lines carrying genomes of people who developed sporadic Alzheimer's disease or in one case carry susceptibility elements (from Craig Venter whose diploid genome is completely sequenced and which is known to harbor Alzheimer susceptibility variants).
To study these problems, we have collaborated with BD biosciences to develop new quantitative methods for generating and purifying neurons made from human embryonic stem cells and induced pluripotent stem cells. We have also developed quantitative methods for evaluating AD phenotypes in these cells. Finally, building upon collaborative work with the Cleveland laboratory, we are developing a potential therapy for ALS (a.k.a. Lou Gehrig's disease) by using human embryonic stem cells to generate human astrocyte progenitors, which are being tested in animal models for safety and effectiveness. We hope that this investigation will lead to clinical trials in the coming years.
Research Focus Areas:
Genetics and Genomics | Membrane Trafficking | Neurodevelopment and Neurodegenerative Disease | Stem Cell Biology
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.
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., Boillée, 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.
Stokin, G.B., Lillo, C, Falzone, T.L., Brusch, R.G., Rockenstein, E., Mount, S.L., Raman, R., Davies, P., Masliah, E., Williams, D.S., and L.S.B. Goldstein. (2005). Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease
. Science 307: 1282-1288.
Gore, A., Li, Z., Fung, H.L., Young, J.E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M.A., Kiskinis, E., Lee, J.H., Loh, Y.H., Manos, P.D., Montserrat, N., Panopoulos, A.D., Ruiz, S., Wilbert, M.L., Yu, J., Kirkness, E., Izpisua Belmonte, J.C., Rossi, D.J., Thomson, J.A., Eggan, K., Daley, G.Q., Goldstein, L.S.B.*, and K. Zhang*. (2011). Somatic coding mutations in human induced pluripotent stem cells
. Nature: 471(7336): 63-67 (PMC3074107). *=co-corresponding authors
Israel, M.A., Yuan, S.H., Bardy, C., Reyna, S.M., Mu, Y., Herrera, C., Hefferan, M.P., Van Gorp, S., Nazor, K.L., Boscolo, F.S., Carson, C.T., Laurent, L.C., Marsala, M., Gage, F.H., Remes, A.M., Koo, E.H., and L.S.B. Goldstein (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
. Nature: 482(7384): 216-220 (PMC3338985).
Ordonez, P., Roberts, E.A., Kidwell, C., Yuan, S., Plaisted, W., and Goldstein, L.S.B. (2012). Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1
. Hum Mol Gen.: 21(12): 2651-2662 (PMC3363339).
Woodruff, G., Young, J.E., Martinez, F.J., Buen, F., Gore, A., Kinaga, J., Li, Z., Yuan, S.H., Zhang, K., and Goldstein, L.S.B. (2013). The Presenilin-1 ∆E9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells
. Cell Reports 5(4): 974-985 (PMC3867011).