Parkinson’s UK — fifty years of discovery
We take a look back at some of the major lightbulb moments over the years, as well as looking ahead to the exciting new wave of therapies emerging from these discoveries.
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On the 26 February 1969, Mali Jenkins founded Parkinson’s UK (The Parkinson’s Disease Society as it was then known), in a one-room office in Putney, London.
Just to be clear, the person in the picture is not Mali Jenkins — that’s astronaut Buzz Aldrin. It turns out, 1969 was not a shy and retiring year. As well as the start of Parkinson’s UK, it also boasted Woodstock, the last public performance of The Beatles, and the Apollo 11 moon landing (pictured).
But back on Earth, Mali’s mission was to improve understanding of Parkinson’s, and improve the lives of people living with the condition.
Since then, we’ve witnessed an explosion in our scientific understanding of Parkinson’s. And the race is now on to translate this understanding into effective treatments. We take a look back at some of the breakthroughs we’ve seen over the past 50 years, and how they are leading us to the treatments of tomorrow.
The dopamine delusion
In the 1960s, scientists knew Parkinson’s was caused by a loss of dopamine-producing cells — resulting in a marked decrease in dopamine levels in the brain — but little else. So, treatments that could replace dopamine seemed the obvious solution.
The first truly effective drug, levodopa, was first tested in people with Parkinson’s in 1961 and remains the main treatment for the condition to this day. Once in the brain, levodopa is converted to dopamine — boosting the supply for cells struggling to make their own, which helps to improve symptoms.
But, as the condition progresses and more brain cells are affected, it becomes more and more difficult to deliver the right amount of dopamine at the right time to keep symptoms under control. Too much and side effects such as dyskinesia can occur. Too little and symptoms take hold.
New and different drug treatments were developed in an attempt to address these issues. In the 1970s, the first dopamine agonists that work by mimicking the action of dopamine emerged. These were followed in the late 80s and 90s by a wave of drugs, such as the combination treatment levodopa/carbidopa and selegiline, which aim to prolong the action of dopamine in the brain.
Research to improve the effectiveness of dopamine-based treatments, and to reduce the risk of side effects is happening right now. But we now know that targeting dopamine alone is not the answer to solving Parkinson’s.
To develop new treatment approaches that could slow, stop or reverse the condition we first need to understand what goes wrong inside the brain.
Scientists across the world have made extraordinary progress in unravelling how and why precious nerve cells become damaged — offering exciting opportunities to save them.
Misfiring mitochondria
In the summer of 1982, hospitals in San Francisco were confronted with a mystery. Young men and women were brought in who had suddenly and inexplicably lost the ability to move and speak, appearing ‘frozen’.
Doctors were mystified, but neurologist Dr Bill Langston recognised the symptoms of advanced Parkinson’s and gave them levodopa, which restored their ability to move and talk.
But what had caused these individuals to develop advanced symptoms of Parkinson’s overnight?
The answer was curious — they had all used synthetic heroin from the same batch, which had been unintentionally contaminated with a manmade chemical called MPTP.
MPTP itself is not toxic but once it reaches the brain it is converted into MPP+ and is sucked up by dopamine-producing brain cells. There, it attacks the mitochondria — the tiny batteries that power our cells. With its energy supply cut off, the brain cell can no longer function.
A few years later, UK scientists examining postmortem brain tissue uncovered problems with mitochondria throughout the damaged and dying brain cells of those with the condition.
Not only are mitochondria in affected cells less efficient at making energy — there are also problems with how these batteries are recycled and replaced.
Mitochondria are busy zipping around cells to deliver energy where it’s needed — no mean feat in large and complex brain cells. This demanding lifestyle means that, just like regular batteries, mitochondria wear out and, when they do, they need to be recycled and replaced with healthy mitochondria.
But in Parkinson’s, this recycling process doesn’t work properly and worn-out mitochondria end up hanging around in cells for too long. Old mitochondria are less efficient at producing energy and also produce noxious chemicals called ‘free radicals’ which contribute to ‘oxidative stress’ — a destructive state which can lead to cell death.
These landmark discoveries suggest that mitochondria lie at the heart of brain cell death in Parkinson’s and researchers across the world are continuing to investigate their role.
A problem protein
Lewy bodies — the spherical clumps found inside brain cells that are the trademark feature of Parkinson’s — were first discovered by Dr Friedrich Lewy, a German-born neurologist, back in 1912.
However, it wasn’t until over 80 years later that scientists really started to unravel the mysteries of their role in the condition. In 1998, researchers in Cambridge identified alpha-synuclein as the major protein that makes up Lewy bodies.
The alpha-synuclein protein is found in cells throughout the body and is found at particularly high levels inside brain cells. Exactly what it does inside cells is still a bit of a mystery, but it’s believed to play a role in releasing neurotransmitters (like dopamine) from cells.
In its normal, healthy form, individual alpha-synuclein molecules float about harmlessly within the cell. But, for some reason, in Parkinson’s alpha-synuclein changes shape and starts to clump together forming sticky bundles.
This abnormal, sticky form of alpha-synuclein can cause problems with a range of important activities inside the cell, including recycling proteins, mitochondrial health and activity, and the release of dopamine.
Experiments have also shown that alpha-synuclein can puncture and escape from damaged brain cells and enter neighbouring cells. Once there, it may then set in motion the chain of events that leads to cell death.
This ‘domino effect’ is now widely believed to be responsible for the spread of Parkinson’s throughout the brain and the progression of the condition itself.
Emerging studies even suggest that the march of alpha-synuclein could begin far outside the brain — in the gut. Sticky bundles of alpha-synuclein, like those found inside brain cells, can be present in the system of nerves that control the gastrointestinal tract and appendix. There is even evidence that people who have their appendix removed, or have a procedure to cut the vagus nerve (the highway between the gut and the brain), may be less likely to get Parkinson’s.
As a result, alpha-synuclein is widely considered to be an important target for treatments that may one day slow or even prevent Parkinson’s.
The genetic jigsaw
Our understanding of Parkinson’s changed forever in 1997. Researchers studying an Italian family with many members affected by the condition discovered a mutation in the gene that provides the instructions for making the alpha-synuclein protein.
The finding that Parkinson’s could be caused by a single genetic misprint was just the start of a whole new scientific frontier.
Further discoveries quickly followed, with researchers identifying changes in other genes including PINK1, Parkin and LRRK2 that could also cause rare inherited forms of the condition. They also provided more evidence that genetics plays a role in the condition.
Major advances in genetic sequencing and computer technology meant researchers were no longer restricted to studying the genetics of rare inherited forms of Parkinson’s in isolated families.
Suddenly, huge collaborative studies involving DNA from thousands of people — called genome-wide association studies — were not only possible but affordable. They allowed scientists to investigate the whole genome and look for differences between people with and without the condition.
These ground-breaking studies identified a host of genetic changes that are more common, but do not cause the condition directly. This means that the people who have them are only slightly more likely to develop Parkinson’s than those who don’t — often by 1–2% at the most.
The most exciting aspect of all these genetic discoveries is that they are steadily revealing a detailed and coherent picture of what causes the condition.
Our genes provide the instruction manual for building and running our bodies. So, each new gene we identify adds a new piece to the puzzle and, gratifyingly, the pieces are beginning to slot neatly together.
Unsurprisingly, many of the genes linked to Parkinson’s so far are involved in mitochondria and protein recycling. Others have been linked to processes such as immunity and inflammation. All open up brand new avenues of research.
Treatments of tomorrow
Thanks to this explosion in our understanding of the biological changes involved in Parkinson’s, a whole host of new, experimental therapies are on the way.
Gene therapies
We’ve heard that genes can contribute to Parkinson’s, but can they help treat it? Researchers investigating gene therapies think so. The idea is to provide the genetic instructions cells need to change their fate. This could be by replacing a faulty gene with a functional one or providing the instructions the cell needs to make certain protective factors. A number of different types of gene therapy are being explored for Parkinson’s. Initial trials in the early 2000s showed promise and this continues to be an active area of development.
Immunotherapies
Immunotherapies take inspiration from our immune systems to create treatments. Scientists have created manmade antibodies in the lab that can recognise and remove sticky alpha-synuclein. By targeting the rogue protein believed to be responsible for the spread of problems through the brain, they aim to stop the progression. Initial trials of the first immunotherapies started in 2012.
Stem cells
For many, stem cells offer what seems the simplest and most obvious solution. That’s because they can be used to grow new, healthy brain cells that could be transplanted into the brain to replace the cells lost and damaged in Parkinson’s. Initial transplantation trials, with foetal tissue, took place in the 1990s and produced mixed results. The first trials using stem cells got underway in the past few years.
Despite the media hype and hope surrounding stem cells, there are many unanswered questions remaining around their safety and effectiveness. Research is continuing in earnest so we’ll no doubt be hearing more about stem cell therapy over the coming years.
Growth factors
Growth factors are naturally occurring molecules that support the development, growth and survival of our brains. Their extraordinary properties make them an exciting prospect for developing new treatments that could help repair damaged brain cells. The first clinical trials in people with Parkinson’s were carried out in the mid-1990s. Getting these large, complex molecules to the right part of the brain is a challenge. However, advances in technology and surgical techniques mean we could be close to solving these issues.
In February 2019, we heard the results of a five year clinical trial testing whether the growth factor GDNF could slow, stop or reverse Parkinson’s. Uniquely, GDNF was infused directly into the brain using pioneering surgery and a purpose-built delivery system. Unfortunately, the primary results were negative, but the work opened up a whole new avenue for drug delivery and the potential for growth factors in nerve cell survival.
Personalised medicine
Huge advances have been made in our understanding of Parkinson’s, and many potential treatments have been identified. But so far, there hasn’t been a successful clinical trial for a drug that can slow, stop or reverse Parkinson’s symptoms. Researchers are now thinking that personalised medicine might be the key to achieving this.
Personalised medicine aims to divide and conquer. So, rather than treating everyone with the same therapy, can we choose the right treatments for the right people to give ourselves a better chance of success? Some of the most advanced examples for Parkinson’s have been inspired by recent discoveries in genetics. New drugs called LRRK2 inhibitors have been developed to calm the overactivity of the LRRK2 protein. And these innovative new drugs will be tested in people with Parkinson’s who carry a genetic misprint in the LRRK2 gene.
Virtual Biotech
Finally, to speed up the delivery of life-changing treatments for people with Parkinson’s, we’ve launched the Parkinson’s Virtual Biotech — to seek out new and untapped ideas that could lead to transformational new treatments. We already have three exciting projects underway and aim to launch our first clinical trials through this exciting initiative later this year.
With thanks to Claire Bale.
