Nifty stem-cell engineering sheds light on Parkinson's disease

Researchers at the University at Buffalo may have taken a significant step toward unraveling the way Parkinson's disease assails the human nervous system--thanks in part to a nifty bit of stem-cell engineering.

Scientists led by physiologist Jian Feng took skin cells from healthy control subjects and people with a particular type of Parkinson's disease and transformed them into a type of primordial cell--technically, an "induced pluripotent stem cell." Such iPS cells, as they're known, can be coaxed into developing as almost any type of cell in the body.

Here, they turned into brain cells. And the cells from the Parkinson's patients turned into brain cells that contained a mutated form of the "parkin" gene.

It's normally almost impossible to study brain cells from live Parkinson's patients. But by generating these brain cells in their lab, the scientists were able to avoid invasive brain surgery and observe that mutations of the parkin gene interrupt dopamine behavior and produce more free radicals, thereby destroying dopamine neurons, which is what causes Parkinson's disease.

In 9 out of 10 Parkinson's cases, researchers don't understand why these neurons die. In the remaining 10 percent, however, the mutation of genes such as parkin is the known culprit. And while the study, published this week in the journal Nature Communications, may only be looking at this minority of Parkinson's cases, understanding how the parkin gene works is relevant to the disease as a whole.

The team's findings could help lead to a breakthrough in the development of a drug that, if it can mimic the protective function of parkin, has the potential to cure this and even other forms of Parkinson's.

The team's method is also a breakthrough because, asFeng says in a school news release, looking inside the brain's complex circuitry has until now been too invasive: "Before this, we didn't even think about being able to study Parkinson's disease in human neurons."

Human neurons are important because researchers believe they have unique vulnerabilities not seen in animals. (Feng adds that our large brains may require more dopamine to control bipedal, as opposed to quadrupedal, movement.)

The team at Buffalo first got a glimpse of how they might generate these neurons in 2007, when researchers in Japan became the first to turn human cells into IPS cells. These are similar to embryonic stem cells, but don't require the destruction of embryos, and instead can be created from the cells of a mature individual.

This accomplishment, Feng says, is advancing not only the study of Parkinson's but other neurological diseases simply by enabling researchers to non-invasively study the disease at its cellular level. "It finally allowed us to obtain the material we needed to study the disease."

By turning these patients' skin cells into dopamine neurons with parkin mutations, Feng and his colleagues were able to see that, once mutated, these cells no longer control how dopamine behaves, which directly hinders what Feng calls the "neural computation" necessary for movement.

Furthermore, the cells are no longer able to control the production of monoamine oxidase (MAO), which can be toxic and, at high levels, appear to contribute to oxidative stress, which can kill dopamine neurons. Maintaining the protective function of parkin, then, could be key to finding a cure for Parkinson's disease.