WENBO ZHOU, Ph.D.

         My research interests focus on the understanding how genetic mutations cause dopamine neuron death and lead to Parkinson's disease (PD). In recent years, several genes have been identified linked to familial form of PD. These genes include a-synuclein, Parkin, DJ-1, PINK1, and LRRK2. We have found that mutant -synuclein leads to abnormal protein aggregation and causes apoptotic cell death in the dopamine neurons. By mutation analysis, we have found that tyrosine at position 39 in the human -synuclein is the most important residue in initiating protein aggregation. Transgenic mice harboring tyrosine-to-cysteine mutation develop motor and cognitive function deficits as well as a-synuclein protein inclusions in the brain.

         We are currently studying other genes linked to PD. We have found that overexpression of DJ-1 protects dopamine cells from oxidative stress-induced toxicity through increasing the gene expression of glutathione, while knock down the endogenous DJ-1 protein renders cells more susceptible to oxidative stress. Furthermore, overexpression of DJ-1 prevents mutant -synuclein induced protein aggregation and neurotoxicity by upregulating heat shock protein 70. Manipulating the endogenous expression levels of DJ-1 could be a novel treatment for PD.

         Another area of my interest is the efficient generation of dopamine neurons from embryonic stem (ES) cells. Collaborating with Dr. Curt Freed, we have modified ES cells by inserting green fluorescent protein (GFP) gene into the dopamine neuron specific gene locus. The ES cells differentiated dopamine neurons could be isolated by GFP marker and be transplanted to animal models of PD. Optimizing the production and purification of dopamine neurons from human ES cells could potentially used for the treatment of PD.

Representative Publications:

Zhou, W., Jiang, Z.H., Ni, Z.M. and Zhou, C.F. Synaptic connections between the embryonic entorhinal transplants and their host of adult rats. Chinese Journal of Physiology Sciences, 10 (1994) 193-201.

Zhou, W. and Zhou, C.F. Axonal tracing using HRP in postfixed brain: light and electron microscopical studies. Chinese Journal of Neuroscience Research, 3 (1996) 9-14.

Zhou, W., Jiang, D, Raisman, G. and Zhou, C.F. Embryonic entorhinal transplants partially ameliorate the deficits in spatial memory in adult rats with entorhinal cortex lesions. Brain Research, 792 (1998) 97-104.

Zhou, W., Raisman, G. and Zhou, C.F. Transplanted embryonic entorhinal neurons make functional synapses in adult host hippocampus. Brain Research, 788 (1998) 202-206.

Hurlbert, M.S., Zhou, W., Wasmeier, 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 (1999) 649-651.

Zhou, W., Hurlbert, M.S., Schaack, J., Prasad K.N. and Freed C.R. Overexpression of human -synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells. Brain Research, 866 (2000) 33-43.

Zhou, W., Schaack, J., Zawada W.M. and Freed C.R. Overexpression of human -synuclein causes dopamine neuron death in primary human mesencephalic culture. Brain Research, 926 (2002) 42-50.

Zhou, W. and Freed, C. R. Tyrosine-to-cysteine modification of human -synuclein enhances protein aggregation and cellular toxicity. Journal of Biological Chemistry, 279 (2004) 10128-10135.

Alvarez, E., Zhou, W., Witta, E. and Freed, C.R. Characterization of the Bex gene family in humans, mice, and rats. Gene, 357 (2005) 18-28.

Zhou, W. and Freed, C.R. DJ-1 upregulates glutathione synthesis during oxidative stress and inhibits A53T -synuclein toxicity. Journal of Biological Chemistry, 280 (2005) 43150-43158.