Parkinson's disease affects millions of people worldwide. Although the symptoms can be treated, there is no known cure. Scientists are investigating how regenerative medicine and stem cell science could be used to treat or prevent the disease.
Boxer Muhammad Ali, actor Michael J. Fox and Pope John Paul II all suffer from Parkinson's disease.
Dopamine-producing nerve cells (labelled red and green) made from iPS cells created from a Parkinson's patient
People with Parkinson's disease don't have enough dopamine – a chemical that allows messages to be sent to the parts of the brain that control movement. The disease kills dopamine-producing nerve cells, or neurons, in part of the brain called the substantia nigra. Parkinson’s is also linked to formation of clumps of a protein called alpha-synuclein in the brain. These abnormal protein clumps are called Lewy bodies.
As dopamine nerve cells die, Parkinson’s patients develop tremors and rigidity, and their movements slow down. They might also lose their sense of smell or suffer from sleep disorders, depression, constipation and sometimes dementia in the later stages of the disease.
Scientists are still baffled by what causes Parkinson's. In about 1 in 10 cases, it is caused by an inherited genetic problem that affects production of the alpha-synuclein protein. What causes the remaining 90 per cent of cases is not clear. It mainly affects people over 40 but can appear in younger people. Men are more at risk than women. Some research has made a link with pesticides, while smoking and coffee appear to reduce the risk of getting the disease, though it is not known why.
Current treatments for Parkinson’s include the drug Levodopa, which was discovered in the 1960s. It is converted into dopamine in the body, so it acts as a stand-in for the lost dopamine-producing neurons. Some other drugs act like dopamine to stimulate the nerve cells. Patients are also treated with occupational therapy, physiotherapy, healthy diet and exercise. Surgery, such as deep brain stimulation with implanted electrodes, is used to treat advanced symptoms.
These treatments relieve the symptoms of Parkinson's disease, but do not slow down or reverse the damage to nerve cells in the brain. Over time, the symptoms often get worse despite treatment. By the time patients are diagnosed with Parkinson’s they have often had the disease for years and have lost most of the critical nerve cells. Tests that detect Parkinson’s earlier may help, but scientists are searching for a way to replace the damaged cells.
Although the underlying cause of Parkinson's disease is unknown, scientists do know which cells and areas of the brain are involved. Researchers are already using stem cells to grow dopamine-producing nerve cells in the lab so that they can study the disease. Because a single, well-defined type of cell is affected, it may also be possible to treat Parkinson’s by replacing the lost nerve cells with healthy new ones.
Replacing lost cells
Doctors and scientists think cell replacement therapy will work because of the results of transplantation studies done in the 1980s. Scandinavian scientists took cells from the adrenal glands of four Parkinson’s patients and transplanted them into the patients’ brains. The adrenal glands sit on top of the kidneys and contain some cells that release dopamine and similar substances. After the transplants, there was some improvement in the patients’ condition, but it was only minor and did not last long. This was the first time dopamine-producing tissue had been transplanted into the human brain. In later experiments, Swedish, American and Canadian researchers have transplanted dopamine-producing neurons from human fetuses into animals and human patients, with major improvements in some cases but only modest changes in others However, there were some side effects in one group of patients and in some cases the disease spread to the transplanted fetal cells more than a decade after surgery.
Scientists still hope that introducing young cells into the brain could delay the onset or progress of Parkinson’s disease, but not enough fetal tissue is available to treat the large numbers of Parkinson’s patients, and the use of foetuses also raises ethical questions. Stem cells could offer an alternative source of new cells for Parkinson’s patients:
Understanding the disease and developing new drugs
Transplantation is not the only application for stem cells. Scientists are making iPS cells from patients with Parkinson’s disease, and using these stem cells to produce diseased neurons in the lab. The neurons act as a powerful tool to study how Parkinson’s disease works and to test substances that could be developed into new drugs to treat the disease.
Stem cell treatments for Parkinson's are still in the early stages of development. Some of the most important recent advances include work on methods for making dopamine-producing neurons in the lab; research on how to improve the effectiveness of transplants and avoid side effects; and studies investigating how the disease works and how cells can help with the development of new drugs.
Cell replacement research: some recent examples
USA-based researcher Lorenz Studer and his colleagues have recently succeeded in making highly efficient dopamine-producing neurons from human embryonic stem cells and have transplanted them into the brains of rats and mice with Parkinson's disease. The cells did not multiply abnormally and improved some symptoms. The researchers also transplanted the neurons into monkeys to show that they would survive and function in larger animals. Work is needed before tests can begin on human patients: the neurons need to be made in sufficient numbers to be effective, and produced in a way that ensures the cells are safe. The scientists hope early clinical trials may be able to start in 2014 or 2015.
Anders Björklund and others in Sweden and Italy have taken human skin cells and converted them directly into dopamine-producing neurons. Whether these neurons survive and improve the symptoms of the disease when transplanted into an animal is not yet known. The long-term goal is to make dopamine-producing neurons from patients' own skin or hair cells.
Anne Rosser and colleagues at Cardiff University, UK are exploring ways to help transplanted nerve cells survive inside the brains of Parkinson's patients.
Disease and drug research: a recent example
Scientists are using iPS cells to investigate the genetic problems that make some people susceptible to Parkinson's. Tilo Kunath’s research group in Edinburgh, UK, is doing this by making iPS cells from a mother and daughter. The mother has Parkinson’s, but her daughter did not inherit the genetic problem. By comparing the ability of the different iPS cells to make neurons and examining those neurons closely, the researchers hope to discover more about how the disease works and to find new drugs.
Stem cell therapies for Parkinson’s disease are not yet ready for use in patients. Much work still needs to be done before clinical trials can go ahead. For now, the main challenges for scientists are:
Video of Michael J Fox describing Parkinson's disease
Interview with Lorenz Studer
NeuroStemCell, a European project working on Parkinson’s disease
Fact sheet about research by Anne Rosser at Cardiff University
Press release about Tilo Kunath’s iPS cell research on Parkinson’s in Edinburgh
News story about research by Anders Bjorklund at Lund University
Podcast from The Naked Scientists on using iPS cells to study Parkinsion's
Michael J. Fox Foundation
European Parkinson’s Disease Association
Lead image or neurons grown from embryonic stem cells by Sally Lowell. Alpha-synuclein structure from Wikimedia Commons.
Picture of green nerve cells by Tilo Kunath. Dopamine-producing cells by Tilo Kunath and reproduced with permission from Devine MJ, Ryten M, Vodicka P, Thomson AJ, Burdon T, Houlden H, Cavaleri F, Nagano M, Drummond NJ, Taanman JW, Schapira AH, Gwinn K, Hardy J, Lewis PA, Kunath T. 2011. Parkinson’s disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nature Communications 2:440. doi:10.1038/ncomms1453.
Michael J Fox photograph by Thomas Atilla Lewis.