The Parkinson’s Disease Society is committed to finding a cure for Parkinson’s – to allow people to live a life that is free from the symptoms of the condition. As there may be many causes, there is unlikely to be a single cure. A key component of the development of a cure is obtaining a greater understanding of what happens when a nerve cell dies. This information will help us to design new and novel treatments which will slow down, halt or reverse the process of nerve cell death and therefore overcome the symptoms of the condition. The PDS is currently investing over £10million into identifying the causes of the condition and how we may use this information to develop more effective treatments. Here are details of some of the key projects that are currently being funded.

What’s the link between nerve cell death and a decrease in the energy within the cell in Parkinson’s?

Dr Alex Whitworth, University of Sheffield (Cost: £99,881 over 36 months)

We know that Parkinson’s is caused by the progressive death of certain nerve cells in the brain. However, we still don’t know the reasons why the cells die. So scientists are working hard to answer three main questions:

• What causes Parkinson’s?

• Why are particular nerve cells vulnerable?

• How does the disease develop?

By answering these questions, we are optimistic of finding better ways of treating the condition, and, ultimately, a cure.

A lot of research suggests that tiny batteries in cells might play a vital part in Parkinson’s. These batteries are called mitochondria and they are central to the life and death of cells. Nerve cells are a real challenge for mitochondria. This is because the cells are very long – up to one metre in length in humans, and have a high demand for energy. So the mitochondria have to whizz around different parts of the cell to supply much-needed energy in the right place and at the right time.

The mitochondria do this by going through a constant cycle where they split apart and then come together again. This cycle is known as fission-fusion. The latest studies have shown that problems with fission-fusion mean the mitochondria can’t move around the cell properly and this triggers the cells to self-destruct and eventually die.

This research project will investigate how altered fission-fusion of mitochondria is linked to the nerve cell death seen in Parkinson’s. Recently scientists have shown that two genes involved in inherited Parkinson’s, called parkin and PINK1, somehow keep the mitochondria in good working order. It is suggested that these genes work together with other parts of the fission-fusion machinery to move mitochondria around the cell. So any defects in the nuts and bolts of the machinery will lead to nerve cell death. this research project is designed to test this theory.

What key factors are responsible for nerve cell death?

Dr Frank Hirth, Kings College London (Cost: £184,696 over 36 months)

The mitochondria are of vital importance for the nerve cells and generate energy through a chain of chemical reactions. However, these reactions are never ‘clean’ and produce hazardous things called free radicals  Too many of these free radicals are bad for the cell. If they pile up, they put the cell under a lot of strain or ‘oxidative stress’. Scientists think this might be fatal for nerve cells. However, there is a lack of conclusive evidence and a direct link needs to be proven. This study will expose dopamine-producing nerve cells to chemical and genetic damage. This will cause the mitochondria not to work properly and lead to oxidative stress. We will then look at whether the nerve cells are more likely to die. If the results from these experiments support this theory, this will open doors to understanding the different pathways involved in nerve cell death. This will assist scientists in discovering new ways of rescuing or protecting nerve cells in people with Parkinson’s.

Nicotine-related substances – a potential treatment for Parkinson’s?

Dr Stephanie Cragg, University of Oxford (Cost: £177,041 over 36 months)

Despite having been introduced almost 40 years ago, levodopa is still the most common treatment for Parkinson’s. Although initially very effective, levodopa loses benefit with time and is troubled by side effects. Scientists are therefore keen to develop other treatments with fewer side effects.

Nicotine influences the working of dopamine, the chemical that is decreased in Parkinson’s, in the normal healthy brain, and nerve cells that make dopamine can also react to nicotine. This research team is interested in a group of chemicals called nicotine-related substances. These substances may have two possible benefits for nerve cells. They might:

¨                  boost the amount of dopamine being produced to help relieve the symptoms

¨                  protect the nerve cells from further damage – that is, to stop the progression of Parkinson’s

This research plans to test whether nicotine-related substances can act on nerve cells and boost dopamine production. The knowledge and outcomes from this research will inform the design and development of drugs that mimic the effects of nicotine with minimal side effects. This will ensure a more effective treatment for Parkinson’s in the short term, but may also have longer term effects to halt the process of nerve cell death.

How alpha-synuclein and nitric oxide synthase cause nerve cell death

Dr Richard Wade-Martins, University of Oxford (Cost: £171,423 over 36 months)

Over recent years, two big themes have emerged in Parkinson’s research – the role of a protein called alpha-synuclein and an enzyme called nitric oxide synthase (NOS). Scientists now know that the alpha-synuclein gene is involved in the rare inherited type of Parkinson’s. Abnormal alpha-synuclein protein is also a key component of Lewy bodies. These are small round clumps of debris found in nerve cells of people with Parkinson’s. Scientists are still figuring out why these clumps form and the importance of alpha-synuclein in how this happens. They think it may have something to do with how cells get rid of old or damaged proteins.

On the other hand, the enzyme NOS influences the amount of stress a cell is placed under. The generation of toxic free radicals may damage nerve cells and cause them to die. This research will study how alpha-synuclein  and NOD contribute towards cell death. This information will permit us to some of the pivotal processes that cause cell death and may therefore allow us to target new drugs to prevent this from happening.

Can human stem cells repair the brains of rats?

Dr Maeve Caldwell, University of Bristol (Cost: £170,649 over 36 months)

Stem cell therapies potentially offer great promise to people with Parkinson’s. The goal of stem cell research is to replace dead dopamine-producing nerve cells with new, healthy cells. This would restore the supply of dopamine in the brain and allow the brain to work properly again.

Scientists are working hard to establish a possible stem cell treatment for Parkinson’s. Unfortunately, we are running into many obstacles. For example, we are still trying to work out the best source of stem cells, how to grow large quantities of high-quality cells in the laboratory and how to stop cells from dying once they are transplanted into the brain. To tackle these problems, stem cell research is being carried out in many different avenues.

This project plans to study how human stem cells can be used to treat rats with symptoms similar to Parkinson’s. The stem cells to make a protein called Lmx1a that appears to influence how the cell behaves. This may help human stem cells turn into dopamine-producing nerve cells. These cells will be transplanted into the brains of rats with Parkinson-like symptoms. Any changes in the symptoms of the treated rats will tell us whether the transplanted cells are having a beneficial effect.

This project will lead to a major advance towards building our understanding of how stem cells are changed into nerve cells and the proteins required to help them stay alive. If successful, we will establish a way of growing large amounts of dopamine-producing nerve cells that live longer when transplanted into animals.

Discovering drugs that slow down the progression of Parkinson’s

Dr Oliver Bandmann, University of Sheffield (Cost: £184,287 over 36 months)

At the moment, there is no cure for Parkinson’s and existing therapies only ease the symptoms. Unfortunately, there is also no treatment that can stop dopamine–producing nerve cells from dying. For that reason, there is a great need to develop new medicines that slow down the rate at which Parkinson’s progresses. This kind of treatment is called a disease-modifying therapy and our research team is focused on finding drugs which may have these properties.

A big problem in Parkinson’s is that the ‘batteries’ of the cell, called the mitochondria, don’t work properly. If the mitochondria don’t work properly, our cells will die. In some people with Parkinson’s, there seems to be something wrong with the mitochondria, not only in the brain, but also in other cells of the body, such as the skin cells. However, nerve cells are very fragile and that is why these are the main cells to die in Parkinson’s.

This study is based on the fact that that the problems with the mitochondria are also seen in other cells in the body, such as skin cells, and these may be used to discover new drugs that will slow down or even stop the nerve cells from dying. Skin biopsies will be taken from people with Parkinson’s who have a specific genetic mutation. The skin cells can be grown in the laboratory and used to screen around 2,000 different drugs to see if they are effective in repairing the problems with the mitochondria.