BioEd Online

In people with Parkinson's disease, a specific type of neuron dies, leaving others relatively unaffected — but why? A study published by Nature today¹ has pinpointed why these particular cells are so vulnerable. The finding suggests that a drug approved to treat another condition could help to slow the progression of the disease.

The affected neurons, which release a neurotransmitter called dopamine, are in a brain region involved in motor function, called the substantia nigra. As the cells die, patients gradually lose control of their movements.

Researchers had suspected that the cells are killed by oxidative stress — a build-up of toxic oxygen-containing molecules that occurs when a cell's energy-producing organelles, or mitochondria, are over-worked. But no-one knew why the dopamine-releasing neurons of the substantia nigra were specifically targeted.

These neurons are unusual in that they continuously generate rhythmic electrical activity. Ion channels in cell membranes that are opened by this innate pacemaking allow a constant flow of calcium ions into the cells. Calcium enters most types of cell only in short bursts.

Because calcium levels are tightly regulated inside the cell, the ions must be forced out again — a process that requires energy. James Surmeier, a neurophysiologist at Northwestern University in Chicago, Illinois, and a co-author of the study, wondered whether this was placing the Parkinson's-affected neurons under extra stress.

Stressed-out cells

To test the idea, Surmeier and his colleagues engineered mice to express a fluorescent protein that is sensitive to the oxidation state of a cell. They expressed the protein in the mitochondria of dopamine-producing neurons.

When the researchers examined the brains of the mice, they found that the dopamine-releasing neurons in the substantia nigra were indeed under greater oxidative stress than those in a neighbouring brain region. This stress dropped when the team blocked calcium from entering the cells.

The researchers also found that the neurons had a defence mechanism. The cells routinely responded to oxidative stress by opening further ion channels, called uncoupling proteins, in the mitochondrial membrane.

Mice with a mutation in DJ-1, a gene associated with early-onset Parkinson's disease in humans, expressed lower levels of some uncoupling proteins than did normal mice, suggesting that the mutation leaves the neurons less able to defend themselves when under stress.

Surmeier and his colleagues have also showed that the neurons don't need the extra calcium for their pacemaking activity, so the team suggests that drugs capable of blocking calcium channels — such as isradipine, which has already been approved for treating high blood pressure — may prove to be a useful treatment for Parkinson's.

Previous research from Surmeier's group has indicated that the drug could make Parkinson's-affected neurons less vulnerable to stressors², and a phase II study testing the tolerability of the calcium-channel blocker in people with Parkinson's is already underway. The results should be available in mid-2011, says Surmeier. After that, the next step will be to assess whether the treatment works; if it does, it would be the first medication to slow the progression of the disease, he adds. Until now, drugs have treated only the symptoms, but they don't stop neurons from dying.

Medicine for mutations

"The story is compelling, but there are still some loose ends," says Bingwei Lu, a neuropathologist at Stanford University School of Medicine in California. For example, the authors have not yet demonstrated explicitly that uncoupling proteins are critical for the process of the disease, nor have they pinned down the exact molecular mechanisms involved, he says.

Flint Beal, a neurologist at Weill Cornell Medical College in New York City, warns that DJ-1 mutations are a rare cause of Parkinson's disease, so plugging calcium channels may not yield the same benefit for other forms of the condition. Nevertheless, Beal sees the study as an important advance. "We need better drugs to actually treat the underlying disease process," he says. "This therapeutic approach has the potential to do just that."