Parkinson’s disease

Parkinson’s disease is a common age-related disorder of the brain and body. There are well over 100,000 people with Parkinson’s in the UK, and the social and economic impacts of the disease are set to rise as the elderly population increases. Parkinson’s is a progressive disease, and although the causes of many cases are unknown, some forms have a genetic origin.

Many of the movement difficulties experienced by people with Parkinson’s arise from the malfunction and death of nerve cells in the brain that make and release a chemical called dopamine. Because of this, most current treatments for the movement symptoms of Parkinson’s rely on drugs that replace or mimic the dopamine that is lost from the brain.

However, the long-term use of these drugs is often associated with serious side-effects, like uncontrolled movements, and they do not stop the disease progressing. There is a pressing need to find new and better treatments for Parkinson’s.

The development of alternative treatments is greatly challenged by the fact that little is known about exactly how and when dopamine-producing nerve cells (known as ‘dopaminergic neurons’) in the healthy brain produce electrical signals to control action from moment to moment. Even less is known about how the signals relayed by dopaminergic neurons change during progression of the disease, especially as it relates to the genes important in Parkinson’s.

Some theories suggest that the electrical activity of dopaminergic neurons is like a metronome, and that these neurons produce a steady level of dopamine to aid movement. However, Professor Magill has exciting new evidence that dopaminergic neurons can precisely vary their electrical activity in time with movement, in effect producing a ‘Morse code’ for action. Furthermore, his team has evidence that both the metronome-like activity and the Morse code-like activity of dopaminergic neurons are abnormal in experimental Parkinson’s.

With Medical Research Foundation funding, Professor Magill will test the link between the behaviour-related activity of dopaminergic neurons and genetic burden and movement difficulties in Parkinsonism. Because these issues cannot be addressed by studying humans alone, the team will use a promising new mouse genetic model of Parkinson’s that captures many of the key features of the human disease.

The use of mice gives access to important controls that are not available in the hospital clinic. In three complementary experiments, Professor Magill and his team will quantify how the metronome-like and Morse code-like activity of dopaminergic neurons are related to movement, how neuron signalling is disturbed in the Parkinson’s model, and whether and how tuning the electrical activity of these neurons back to normal levels restores correct movement.

This research will provide important new knowledge about the functions of dopaminergic neurons in health and disease. It will also put us in a stronger position to provide a rational basis for developing new therapies that are better able to control these neurons and provide improved relief from movement difficulties.