Study Seeks Molecular Cause of Parkinson’s Disease, Subtypes

The resulting cellular models may lend insight into the cause of Parkinson’s disease and pave the way for targeted treatments for patients in two distinct categories: those who experience tremors at rest when first diagnosed and those who do not.

This innovative research is funded by NYSTEM (New York State Stem Cell Science).

Feng is ultimately exploring whether complex human conditions such as Parkinson’s disease have a molecular cause in an individual’s genome.

He is generating midbrain, dopamine-releasing neurons from induced pluripotent stem cells (iPSCs) derived from patients’ skin fibroblasts.

Unlike neurons, the skin fibroblasts are easily accessible cells that can be reprogrammed into iPSCs. iPSCs can differentiate into any other type of cell.

“This research aims to redefine Parkinson’s disease by identifying molecular differences” between these two types of patients, says Feng.

Results could help lead to targeted treatment strategies, as the two types of patients respond differently to the disease.

Patients who initially have tremors at rest generally have a better prognosis and slower progression of disease, compared to those who do not experience tremors at rest when first diagnosed.

Feng will analyze these neurons from both types of patients to detect differences in the expression levels of key genes involved in dopamine function.

Dopamine is a brain chemical that is critical for coordinating movement, but depleted in Parkinson’s disease patients.

In a previous study, when Feng analyzed fibroblasts derived from both types of patients, he found a significant difference in the expression levels of the key dopamine genes.

These genes are highly expressed in midbrain dopaminergic neurons, Feng explains.

“Because the dopaminergic neurons derived from the stem cells contain the same genome as the diseased neurons in the patient’s brain, we believe the experiments will provide very useful information on the cause of Parkinson’s disease,” he says.

The research team will use mRNA profiling and proteomic methods to identify the molecular signature of neurons from each patient group.

The results could help identify biomarkers and pave the way for subtype-specific diagnoses and treatments.

Understanding the underlying pathology of Parkinson’s disease and its subtypes also could help identify neuroprotective strategies to prevent or ward off this complex, degenerative condition.

The novel stem cell technologies that Feng is advancing offer broad potential for understanding the molecular causes of disease in general.

“We can capture an individual genome in an easily accessible cell, such as a skin fibroblast, and then rewire the transcription network in that cell so that the same genome can be directed to embody another cell type—dopaminergic neurons, for example,” Feng explains.

“The same approach can be used to study any human disease, particularly when physical access to the diseased cells is difficult or impossible,” he says.

Feng is collaborating on the project with Zihua Hu, PhD, an instructional specialist in the UB Center for Computational Research and research assistant professor of ophthalmology; Thomas J. Guttuso, Jr., MD, associate professor of neurology; and Rudolf Jaenisch, MD, professor of biology at the Massachusetts Institute of Technology.

Feng directs the Induced Pluripotent Stem Cell Generation facility that generates induced pluripotent stem cells from human skin fibroblasts. It is one of four core facilities of the Western New York Stem Culture and Analysis Center.