Research in my laboratory has focused on the dynamic use of neurotransmitters during movement. We have used the technique of in vivo dialysis to study the release of dopamine, norepinephrine, and serotonin in awake, behaving animals. With these methods, we have shown that dopamine metabolism is increased in striatum and other brain nuclei during motor activity.
In 1988, my neurosurgical colleague, Robert Breeze, MD, and I performed the first transplant of human fetal dopamine cells into a Parkinson patient in the United States. Since that time, we have performed implants on more than 60 Parkinson patients. With support from the National Institutes of Health, we have conducted a double-blind, placebo surgery controlled clinical trial of the transplant method. It was the first placebo controlled trial ever done in the field of Neurosurgery. Results showed that transplants could survive without the need for immunosuppression and could improve objective signs of Parkinson’s disease. That research was published in the New England Journal of Medicine in 2001.
To extend transplantation to more patients, we are developing methods to convert human embryonic stem cells to dopamine neurons. These techniques should make it possible to produce unlimited quantities of dopamine cells for transplant. With these human cells, we have successfully treated animals with a condition similar to Parkinson’s disease. We expect that this stem cell strategy will be available to Parkinson patients in the coming years.
My laboratory is staffed by graduate students, post doctoral fellows, technicians, and faculty. Funding is from NIH grants, organizations like the American Parkinson's Disease Association, and individual philanthropists. The University of Colorado was named a National Parkinson Foundation Center of Excellence in 1995.
Contact me at Curt.Freed@cuanschutz.edu
Zawada, W.M., Zastrow, D.J., Clarkson, E.D., Adams, F.S., Bell, K.P. and Freed, C.R.: Growth factors improve immediate survival of embryonic dopamine neurons after transplantation into rats. Brain Research 786:96-103, 1998.
Zawada WM, Cibelli JB, Choi PK, Clarkson ED, Golueke PJ, Witta SE, Bell KP, Kane J, Ponce De Leon FA, Jerry DJ, Robl JM, Freed CR and Stice SL. Somatic cell cloning-produced transgenic bovine neurons for transplantation in Parkinsonian rats. Nature Med 4:569-574, 1998.
Hurlbert M.S., Zhou W., Wasneier C., Kaddis F.G., Hutton J.C., and Freed C.R. Mice transgenic for an expanded CAG repeat in the Huntington’s disease gene develop diabetes. Diabetes 48:649-651, 1999.
Hurlbert M.S., Gianani R.I, Hutt C., Freed C.R., and Kaddis F.G. Neural transplantation of hNT neurons for Huntington’s disease. Cell Transplantation 8:143-151, 1999.
Clarkson, E.D., Edwards-Prasad, J., Freed, C.R., and Prasad, K.N.: Immortalized dopamine neurons: A model to study neurotoxicity and neuroprotection. Proceedings of the Soc. Exp. Biol and Med.,222:157-163, 1999.
Zhou, W., Hurlbert, M.S., Schaack, J., Prasad, K.N., Freed, C.R.: Overexpression of human a-synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells. Brain Res. 866:33-43, 2000.
Kaddis, F.G., Clarkson, E.D., Bell, K.P., Choi, P.K. and Freed, C.R.: Co-grafts of muscle cells and mesencephalic tissue into hemiparkinsonian rats: Behavioral and histochemical effects. Brain Res. Bull. 51(3):203-211, 2000.
Bjugstad, K.B., Goodman, S.I., and Freed, C.R.: Age of symptom onset predicts severity of motor impairment and clinical outcome of glutaric acidemia type 1. J. Pediatrics 137:681-686, 2000.
Nakamura, T., Dhawan, V., Chaly, T., Fukuda, M., Ma, Y., Breeze, R.E., Greene, P.E., Fahn, S., Freed, C.R., and Eidelberg, D.: Blinded positron emission tomography study of dopamine cell implantation for Parkinson’s disease. Annals of Neurology 50:181-187, 2001.
Clarkson, E.D., Zawada, W.M., Bell, K.P., Choi, P.K., and Freed, C.R.: IGF-1 and bFGF improve dopamine neuron survival and behavioral outcome in Parkinsonian rats receiving cultured human fetal tissue strands. Experimental Neurology 168(1):183-191, 2001.
Freed, C.R., Greene, P.E., Breeze, R.E. Tsai, W.-Y., DuMouchel, W., Ko, R., Dillon, S., Winfield, H., Culver, S.,Trojanowski, J.Q., Eidelberg, D., and Fahn, S.: Embryonic dopamine cell transplantation for severe Parkinson’s disease. New England Journal of Medicine 344(10):710-719, 2001.
Zawada, W.M., Meintzer, M.K., Rao, P., Marotti, J., Wang, X., Esplen, J.E., Clarkson, E.D., Freed, C.R., and Heidenreich, K.A. Inhibitors of p38 MAP kinase increase the survival of transplanted dopamine neurons. Brain Research 891:185-196, 2001.
Ourednik, V., Ourednik, J., Flax, J.D., Zawada, M., Hutt, C., Yang, C., Park, K.I., Kim, S.U., Sidman, R.I., Freed, C.R., and Snyder, E.Y.: Segregation of human neural stem cells in the developing primate forebrain. Science 2001;293:1820-1824.
Bjugstad, K.B., Zawada, W.M., Goodman, S.I., and Freed, C.R.: IGF-1 and bFGF reduce glutaric acid and 3- hydroxyglutaaric acid toxicity in striatal cultures. J. Inherit. Metab. Dis 24:631-647, 2001.
Zhou, W., Schaack, J., Zawada, W.M. and Freed, C.R.: Overexpression of human a-synuclein causes dopamine neuron death in primary human mesencephalic culture. Brain Res 926:42-50, 2002.
Freed, C.R.: Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson's disease? PNAS 99(4): 1755-1757, 2002.
Nahreini P., Andreatta C., Kumar B., Hanson A., Edwards-Prasad J., Freed C.R., Prasad K.N. Distinct patterns of gene expression induced by viral oncogenes in human embryonic brain cells.Cell & Molecular Biology 23:27-42, 2003.
Trott C.T., Fahn S., Greene P., Dillon S., Winfield H., Winfield L., Kao R., Eidelberg D., Freed C.R., Breeze R.E., Stern Y. Cognition following bilateral implants of embryonic dopamine neurons in PD: A double blind study. Neurology 60(12) 1938-1943. 2003.
Bjorklund A., Dunnett S.B., Brundin P., Stoessl A.J., Freed C.R., Breeze R.E., Levivier M., Peschanski M., Studder L., Barker R. Neural transplantation for the treatment of Parkinson’s disease. Lancet Neurology 2: 437-45, 2003.
Freed, C.R., Leehey M.A., Zawada M., Bjugstad K., Thompson L., Breeze R.E. Do patients with Parkinson’s disease benefit from embryonic dopamine cell transplantation? Journal of Neurology 250(Supplement 3) 44-46, 2003.
Ahmadi F.A., Linseman D.A., Grammatopoulos T.N., Jones S.M., Bouchard R.J., Freed C.R., Heidenrich K.A., Zawada W.M. The pesticide rotenone induces caspase-3-mediated apoptosis in ventral mesencephalic dopaminergic neurons. Journal Neurochemistry 87(4): 914-21, 2003.
Zhou W., Freed C.R. Tyrosine-to-cysteine modification of human alpha-synuclein enchances protein aggregation and cellular toxicity. Journal of Biological Chemistry 279 (11) 10128-10135, 2004.
McRae, C., E. Cherin, T.G. Yamazaki, G. Diem, A.H. Vo, D. Russell, J.H. Ellgring, S. Fahn, P. Greene, S. Dillon, H. Winfield, K.B. Bjugstad, and C.R. Freed: Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry: 61:412-420, 2004.
Gordon, P., Yu, Q., Qualls, C., Winfield, H., Dillon, S., Greene, P., Fahn, S., Breeze, R., Freed, C.R., Pullman, S. Reaction Time and Movement Time After Embryonic Cell Implantation in Parkinson Disease. Arch. Neurology: 61:858-861, 2004.
Buytaert-Hoefen, K., Alvarez, E., Freed, C.R.. Generation of Tyrosine Hydroxylase Positive Neurons from Human Embryonic Stem Cells after Coculture with Cellular Substrates and Exposure to GDNF. Stem Cells: 22:669-674, 2004.
Zhou, W. and Freed, C.R. DJ-1 upregulates glutathione synthesis during oxidative stress and inhibits A53T a-synuclein toxicity. J. Biol. Chem. 280 (2005) 43150-43158.
Bjugstad KB, Crnic LS, Goodman SI and Freed CR. Infant Mice with glutaric acidaemia type I have increased vulnerability to 3-nitropropionic acid toxicity. J. Inherit Metabl Dis. 2006 29:612-619