One of the major hurdles for Parkinson’s research is the lack of live dopamine neurons from patients for long-term studies and drug screens. This project will use the newly discovered induced pluripotent stem cell technology to generate unlimited supply of human dopamine neurons with or without parkin mutations. It will greatly help us to understand why dopamine neurons die when parkin is mutated and how we may prevent it.
We will change skin cells from normal subjects and patients with parkin mutations to stem cells by introducing four genes that have been shown to work in this manner. The resulting stem cells will be converted to dopamine neurons using specialized cell culture techniques. Because these dopamine neurons have the same genetic information as the original skin cells, they will be essentially the same as those dopamine neurons in the brain of the original patients and healthy subjects. We will compare these human dopamine neurons to see how the functions of mitochondria are altered by parkin mutations. We will also test whether parkin mutations make human dopamine neurons more vulnerable to Parkinson’s disease toxins that are known to affect mitochondrial functions.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will not only reveal the functions of parkin in human dopamine neurons, but also allow us to identify novel protective strategies to enhance the survival of these neurons when parkin is mutated. We can use the same technique to study other genes linked to the disease, as well as idiopathic Parkinson’s disease.
We expect to generate human dopamine neurons with parkin mutations and their normal counterpart. With these neurons, we will be able to tell whether mutations of parkin significantly increase the expression of mitochondrial proteins involved in the production of free radicals. In addition, we will also know whether parkin mutations make human dopamine neurons more susceptible to Parkinson’s toxins that increase the production of free radicals in mitochondria.
Dr. Feng obtained cells from patients with mutations in the parkin gene and was able to induce these cells to become iPS cells. Coaxing these cells to become dopaminergic neurons has proven difficult, however. In a follow-up study, Dr. Feng is working to generate iPS cells that may be more readily converted into dopaminergic neurons.
As a result of the MJFF award, Dr. Feng received follow-on funding from the National Institute of Neurological Disorders and Stroke (NINDS) (National Institutes of Health) as part of the PD iPS Consortium to generate iPS cells for Parkinson's disease research.