: Parkinson’s disease, mechanism of pathogenesis and novel treatmentGraduate School
: Shanghai Institute of Neurosciences, Chinese Academy of SciencesI have been with the University since
Description of my interests:
My research interests focus on the understanding how genetic mutations cause dopamine neuron death and lead to Parkinson's disease (PD). In last decade, several genes have been identified linked to familial form of PD. These genes include alpha-synuclein, Parkin, DJ-1, PINK1, and LRRK2. We have found that mutant alpha-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 of human alpha-synuclein is the most important residue in initiating protein aggregation. Transgenic mice harboring tyrosine-to-cysteine mutation develop motor and cognitive dysfunction as well as alpha-synuclein protein inclusions in the brain. This novel transgenic mouse model can be used for Parkinson disease modeling and drug screening.
We are studied another PD gene called DJ-1. 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 alpha-synuclein induced protein aggregation and neurotoxicity by upregulating heat shock protein 70. Through drug screening, we have found that histone deacetylase inhibitors such as phenylbutyrate can increase DJ-1 gene expression by 2-3 folds in dopamine neuron culture and mouse brain. In transgenic mice expressing mutant alpha-synuclein, phenylbutyrate treatment led to significant motor and cognitive function improvement, as well as significant reduction in alpha-synuclein aggregation. Drugs that can increase DJ-1 expression could be novel treatment for PD.
We are also interested in the stem cells. Dopamine cell transplantation for PD treatment has been demonstrated feasible and effective. Due to the limit supply of fetal dopamine neurons, we are trying to generate dopamine neurons from embryonic stem (ES) cells. To separate and purify dopamine neurons from a mixture of differentiated stem cells, we have genetically modified ES cells by inserting green fluorescent protein (GFP) gene into the dopamine transporter gene locus. The differentiated dopamine neurons could be isolated by GFP marker. These purified dopamine neurons could be used for gene expression profile studies with DNA microarray.
In last few years, there is a ground breakthrough in the stem cell research. It has been demonstrated that human skin fibroblasts can be reprogrammed to ES-like pluripotent stem cells by expressing four transcriptional factors. Recently, we have generated induced pluripotent stem cells (iPS) cells from human skin fibroblasts using adenovirus based method. The iPS cells are completely free of any viral gene integration. Using this method, we have generated integration-free iPS cells from Parkinson patient fibroblasts. These iPS cells can be induced to differentiate into specific type of cells, such as dopamine neurons, which may be suitable for cell based transplantation therapy. With this method, we are generating neurological disease-specific iPS cells for disease modeling and drug screening.