A step in the right direction for Parkinson’s disease treatment?
In her runner-up article for the Max Perutz Science Writing Award 2013, Clare Finlay, a Phd student at King’s College London, explains her research looking at ways to stop dopamine-producing brain cells from dying in Parkinson’s disease.
It starts small, a seemingly innocuous tremor of one little finger that you attribute to working later than usual or that extra shot of espresso in your morning cappuccino. You ignore it, assume it will resolve itself, but soon you find that you’re typing extra letters on your keyboard; ‘A’s and ‘S’s and ‘W’s. A feeling that something isn’t quite right creeps in to your mind, and only intensifies when your family notices that you’ve started to shuffle slightly when you walk and that your once smiley face is becoming less expressive. So you make an appointment with the doctor to see what the cause might be, and receive the news that it is probably the beginnings of Parkinson’s disease.
Parkinson’s disease is a neurological disorder, characterised by slowness and rigidity of movement and, perhaps more recognisably, a resting tremor. It’s caused by the degeneration of a group of cells in the brain that produce a chemical called dopamine. The job of dopamine in the brain is to balance the activity of two opposing movement-related pathways; the ‘direct’ pathway, which acts as the accelerator and is activated by dopamine, and the ‘indirect’ pathway, which acts as the brake and is inhibited by dopamine.
Just as when you’re driving a car, in a healthy brain this dopamine ensures that the accelerator is engaged and the brake disengaged to allow for a smooth journey. Parkinson’s disease occurs when the body no longer has enough cells to produce sufficient dopamine to maintain this status, so the reverse becomes true. The brain lifts off the accelerator and leans on the brakes, slowing the person down to a crawl. Patients describe feeling as though they are walking in treacle, with slow heavy limbs that fatigue quickly. Their fingers can no longer deftly shuffle a deck of cards or open a jar of peanut butter, but instead move at an infuriatingly slow pace. Later they may find that they freeze mid-step while walking, or struggle to initiate an everyday movement such as getting out of bed.
Since the late 1960s, debilitating symptoms such as these have been treated by replacing the lost dopamine with synthetic alternatives, restoring acceleration and lifting off the brake. It sounds simple, and indeed works well for the majority of patients for several years. However as the disease progresses and more dopamine-producing cells are lost, the connections in the brain alter, causing the circuits to misfire. This can result in sudden involuntary movements when the brain is ‘on’ the dopamine replacement drugs that can be as disruptive to normal life as the classical Parkinson’s disease symptoms when the brain is ‘off’ the drugs. The next step on from this is currently invasive brain surgery, so it is clear that new drug-based treatment strategies are needed.
If we can reduce the need for dopamine replacement drugs we can hopefully delay the onset of the side effects that so often diminish quality of life within a few years of starting treatment. My research seeks an alternative way to rebalance the opposing pathways by targeting glutamate instead of dopamine. Glutamate is an essential chemical for normal brain function but when it is released in large amounts it can cause cells to become over-excited, leading them to malfunction and die. In Parkinson’s disease excess glutamate is not only released in the ‘indirect’ pathway, thereby contributing to the excess braking in the patient’s movements, but also into the precise area that degenerates to cause the disease in the first place, potentially hastening the loss of precious remaining cells. By reducing glutamate release we hope not only to manage the symptoms of Parkinson’s disease but potentially to delay its progression by helping to preserve the dopamine-producing cells that are still left.
The lab that I work in has shown that by activating a family of nerve cell receptors that reduces glutamate release it is possible to protect dopamine-producing cells both in a culture dish and in the living brain. Stopping these cells from dying means that they can still produce the dopamine necessary to balance the accelerator and brake in the brain so movement is preserved. We are now trying to unravel which family member is the most important so we can target it directly.
The work I do is very early stage but hopefully it could lay the foundations for future treatments that will help maintain patients’ independence and allow them to enjoy doing the things they love to do for longer. The causes of Parkinson’s disease are complex, and therefore a cure may still be a distant prospect, but these small steps to treat symptoms and slow disease progression represent an important stride towards an improved quality of life for patients.