Parkinson's Disease

 

What is Parkinson's Disease?

 

Parkinson's disease (PD) is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain. The cause of this cell death is unknown. Early in the course of the disease, as dopamine nerve cells die, Parkinson’s patients develop movement-related symptoms, which include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. Parkinson's disease is more common in older people, with most cases occurring after the age of 50. 

 

Parkinson’s is also linked to the formation of clumps of a protein called alpha-synuclein in the brain. These abnormal protein clumps are called Lewy bodies. 

 

Scientists are still baffled by what causes Parkinson's. In about 1 in 20 cases, it is caused by an inherited genetic problem that affects production of the alpha-synuclein protein. What causes the remaining 95 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

 

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 more advanced cases, especially in those where the drugs are working less well.

 

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 clinical features get worse despite treatment. By the time patients are diagnosed with Parkinson’s they have often had the disease for years and have lost over half of the dopamine cells within the nigra. Tests that detect Parkinson’s earlier may help, but scientists are searching for a way to replace the damaged cells.

 

How could stem cells help?

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, especially in those cases where there is a known genetic cause for the condition. 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 1980-90s. In particular, Swedish, American and Canadian researchers have transplanted the developing nigral dopamine-producing neurons from human fetuses into animals and human patients with PD, with major improvements in some cases but only modest changes in others. These initial studies led on to bigger studies which then reported some side effects in some patients in receipt of such grafts in the form of involuntary graft induced movements - similar to those seen in many patients on long term L-dopa treatment. The basis for this is still debated but may relate to the transplantation of non-DA cells found in the human fetal midbrain grafts. In addition it has also been noted that some patients have also developed some PD pathology in their grafts, even though the transplants are less than 20 years old. This has led to he suggestion that PD may involve a process of disease spread through the passing of abnormal forms of alpha synuclein from one nerve cell to another.

A new study, TRANSEURO, is looking again at fetal human dopamine transplants and aims to address issues of consistent efficacy and avoiding the side effects of the involuntary graft induced movements. This new study will involve a new clinical trial.  

 

Scientists remain optimistic that introducing young cells into the brain could better treat Parkinson’s disease, but not enough fetal tissue is available to treat the large numbers of people with Parkinson’s, and the use of fetuses also raises ethical questions. So at the same time, they are looking at stem cells as an alternative source of new dopamine cells for Parkinson’s patients:

 

• Embryonic stem (ES) cells could be directed to make dopamine-producing neurons, which could be transplanted into patients. Dopamine-producing neurons have been made from both mouse and human embryonic stem cells in the laboratory, and the human cells have recently been shown to have similar effects as the fetal cells in a rat model of Parkinson’s disease.

 

• Induced pluripotent stem (iPS) cells could be made from a patient’s adult skin cells in the lab, and then used to make dopamine-producing neurons. In 2010 scientists in the USA treated rats with neurons made from human skin cells using iPS techniques. The transplanted neurons improved features of Parkinson's disease in the rats. However, mice and rats require fewer neurons than humans and it is not yet clear whether this approach would work in patients. More studies are also needed to make sure the cells are safe and would not cause tumours in the brain, and also do not rapidly develop the pathology of Parkinson’s given they are derived from the patients themselves.

 

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.