Why do brain cells die in Parkinson’s (and how can we stop it)?
Researchers across the globe are looking closely at the key processes involved in the development of Parkinson's, and exploring how unlocking the causes could lead to pioneering new treatments.
In Parkinson’s, certain brain cells that produce dopamine gradually stop working and die. Dopamine is a chemical vital for controlling movement. Movement symptoms like slowness, stiffness, tremors, smaller handwriting, shuffling steps, and reduced facial expression typically appear after about 70% of these cells are lost.
While Parkinson’s is often thought of as a movement disorder, it also causes a range of non-motor symptoms, including loss of smell, constipation, sleep problems, anxiety, depression, and changes in thinking and memory.
Current treatments focus on ‘topping up’ dopamine levels to manage symptoms. But so far there are no treatments that can slow or stop the loss of dopamine-producing brain cells. So as the condition progresses, managing symptoms becomes more challenging, and requires more medication. And with more medication can come more side effects.
To find treatments that can slow or stop Parkinson’s we first must understand why these brain cells are dying. Over the past 50 years, we’ve funded many research projects that have uncovered important clues. These findings are already leading to the development and investigation of potential treatments. But, the full picture remains incomplete.
Let’s look at some of the key processes we think might be involved in Parkinson’s and how new treatments could address them.
Lewy bodies and alpha-synuclein
Back in 1912, one of the first things that scientists noticed about the cells affected in Parkinson’s were large clumps of something visible under the microscope that weren’t present in healthy cells.
These clumps were discovered by a scientist called Friedrich Lewy and were named Lewy bodies.
Further studies showed that Lewy bodies are made up of a tangled mass of misshapen proteins. The most abundant protein is one called alpha-synuclein, which researchers now believe to be involved in the development of Parkinson’s.
In the late 90s, scientists discovered that people who have a genetic change that means they produce too much alpha-synuclein develop a very rare inherited form of Parkinson’s. Professor Maria Grazia Spillantini was one of the scientists involved in this discovery, and since then we’ve funded many of her projects which are looking to understand how alpha-synuclein sticks together and causes damage.
More recent studies have shown that misshapen alpha-synuclein can escape from damaged cells and be taken into their healthy neighbours, leading them to become affected and the condition to spread through the brain.
This has led to alpha-synuclein becoming a major target for drug development. Many researchers and companies are working on treatments that aim to help the brain clear away faulty alpha-synuclein or prevent its spread from cell to cell.
Mitochondria
Mitochondria are the tiny energy-producing batteries that power almost every cell in the body. Most cells contain hundreds or even thousands of them to generate the energy they need to do their work.
Dopamine-producing brain cells are some of the most energy-hungry cells in our bodies because they are large and extremely busy.
In the late 1980s, we funded scientists in a project which discovered that mitochondria in the cells affected by Parkinson's stop working properly. These mitochondria can no longer produce energy efficiently and start to become toxic to the brain cells.
Further proof of the important role that mitochondria play came when research into the genetics of the condition identified key genes - PINK1 and Parkin - that cause rare, early-onset forms of the condition. Both of these genes play an important role in the cell’s ability to clear away mitochondria that aren’t working properly.
Finding ways to help failing mitochondria is now a promising avenue of research to create new and better treatments for Parkinson’s. One particularly exciting project that we’re funding is being led by company NRG Therapeutics. The company has developed a new potential drug that patches up damaged mitochondria to prevent brain cell death. Their early experiments in the lab have been very successful, and NRG Therapeutics have recently received more funding so they can get ready to test the potential therapy in people for the first time.
Read our blog about mitochondria and the work underway to find new treatments.
Waste recycling
In most neurodegenerative conditions there’s evidence that brain cells become clogged up with old or damaged proteins, stopping them from doing their job properly. In Parkinson’s, this could be alpha-synuclein and other misshapen proteins in Lewy bodies, or damaged mitochondria.
One way cells are kept ‘clean’ is through their own recycling system, made up of cellular machines called lysosomes. These are self-contained sacks that carry enzymes, tools that can break down old or unwanted materials within the cell.
Cellular recycling is carefully controlled by different genes and proteins inside our cells. But if this process is not working efficiently it can lead to waste building up which can cause damage. Drugs that can boost the cell’s ability to recycle waste could help reduce this damage.
We have joined forces with Cure Parkinson’s to co-fund a clinical trial looking at the potential of a cough medicine called ambroxol to treat Parkinson’s.
Ambroxol boosts levels of an enzyme called GCase, which is known to help clear away waste products which have gathered in brain cells. It’s thought that ambroxol may help improve the body’s ability to clear away alpha-synuclein and prevent damage to brain cells.
Read more about the Ambroxol study.
Inflammation
Inflammation is a key process for keeping us healthy as our immune cells attack and get rid of foreign invaders. However, too much inflammation can be damaging to cells.
In Parkinson’s, studies funded by us and others have shown that there’s more inflammation in the brain areas affected by the condition. Scientists believe this may play a role in damaging the dopamine-producing cells affected in Parkinson’s, speeding up the rate at which the cells die.
As a result, the search is now on to find therapies that can reduce inflammation in the brain, as these could have the potential to slow or stop the progression of the condition.
We’re funding a pioneering clinical trial to test a potential new drug that aims to reduce inflammation in the brain. The trial is being carried out in people with a sleep disorder that is associated with an increased risk of developing Parkinson's in the future. It’ll look at levels of inflammation before and after treatment by using a special brain scan technique. The hope is the drug could help slow or even prevent the progression of Parkinson’s.
Find out more about the Syntara trial.
What we still don’t know
While research has uncovered vital clues to the causes of brain cell death in Parkinson’s there are still many outstanding questions:
- How do these different issues - faulty cell recycling systems, damaged mitochondria, overactive inflammation and misshapen alpha-synuclein - interact and influence each other?
- What goes wrong first and which things come later?
- Is this different depending on the person, and if so does that affect their symptoms or progression?
- Will people need personalised treatments focused on that particular problem?
- What else is going on? Are there other important processes we should be focusing on?
Answering these questions remains a key focus. Finding answers will unlock new ways to slow, stop or reverse the condition. And we’re funding research that’s looking at all 4 of these issues.
One major project which aims to do this is a collaboration we’re leading between Imperial College London and 6 pharmaceutical companies, called Landmark.
This visionary project is using tissue from the Parkinson’s UK Brain Bank based at Imperial and using pioneering new analysis techniques to look at individual brain cells within the donated tissue. The project will provide more information than ever before on what is happening to the brain cells that are lost in the course of the condition, and will help us fill in critical gaps in our understanding.
Learn more about the pioneering Landmark programme.
How far away are we from new treatments?
Researchers, companies and patient organisations are working to create new treatment approaches that address the fundamental problems that cause brain cell death in Parkinson’s. Some of these potential therapies are already being tested in clinical trials, others will be reaching this point in the next couple of years.
There is also huge progress being made to unlock the remaining mysteries of why and how Parkinson’s develops. The new knowledge this is generating will lead to new opportunities for treatments to feed into this exciting landscape.
It’s not possible to put a precise timescale on when we will have treatments that can protect brain cells and slow or stop the progression of Parkinson’s. But we are determined to continue doing everything we can to get there as quickly as possible.
Read more about the research we're funding
Understanding the causes of Parkinson's will open up opportunities for new and better treatments. We're funding critical research to help us find the answers.