Trials to treatments: targeting mitochondria
We know that, in Parkinson’s, the batteries that power our cells don’t work as well as they should. It’s now up to researchers to find drugs that target these dysfunctioning batteries, known as mitochondria, and protect the nerve cells from energy failure and death.
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A chance discovery
It takes a lot of power for our brains to work properly. Making up just 2% of our total body weight, they use 20% of all the body’s energy reserves. So out of all the organs in the body, the brain is particularly reliant on the work of the tiny batteries found in every cell — the mitochondria.
It’s perhaps not surprising then that many neurodegenerative conditions have been linked to mitochondria going wrong. And Parkinson’s is no exception.
It was a freak incident in 1982 that gave the first clue that mitochondrial dysfunction may be linked to Parkinson’s. People who had taken heroin suddenly lost the ability to speak or move, appearing “frozen”. The symptoms were reversed by levodopa. It turned out it was a contaminated batch of heroin, containing the chemical MPTP. This man-made chemical was taken up by dopamine-producing brain cells and attacked the mitochondria, cutting off the cell’s energy supply.
Since then, there has been lots of research showing that mitochondria play a role in both the onset and progression of Parkinson’s. The race is now on to turn this knowledge into treatments that can stop Parkinson’s.
The powerhouse of the cell
So new treatments targeting mitochondria could help treat Parkinson’s — let’s find out how these energy-producing batteries work.
The mitochondria are the powerhouse of the cell. They take nutrients from food and oxygen to produce a type of energy currency, a molecule called adenosine triphosphate, or ATP.
Every part of our cells requires energy. To keep them working, mitochondria must constantly produce ATP while travelling the length of the cell — no mean feat in large and complex nerves. 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. As we’ll see, this recycling process can go wrong in Parkinson’s.
But it’s not just energy production that mitochondria are responsible for. They also have an important role in helping brain cells communicate — and this involves managing calcium.
Calcium is essential for the body to work properly, and is particularly important for brain cells. As an electrical signal travels down a nerve, it triggers calcium to flood into the cell.
To reset the nerve cell so it can continue to send signals, the levels of calcium need to be reduced — this is where mitochondria come in. Mitochondria can temporarily store calcium until it can be removed. But in times of stress, too much calcium might build up inside the mitochondria — this is bad news as researchers believe it could lead to the loss of brain cells.
Mitochondria and Parkinson’s
Since the events in San Francisco in the 1980s, we’ve learnt a great deal about mitochondria and brain cell death in Parkinson’s.
Dopamine-releasing nerves in the brain are relatively large, always active and have connections with many other nerves. It takes a lot of energy to run them, and they appear to be particularly sensitive to problems with mitochondria.
And we now know that in most people with Parkinson’s, there are various problems with mitochondria:
1. Genetic links
The Parkinson’s-associated genes PINK1 and Parkin help regulate the recycling of the old, worn-out mitochondria. Changes in these genes can mean that the recycling process doesn’t work properly and the worn-out mitochondria end up hanging around in cells for too long. Old mitochondria are less efficient at producing energy and they also produce harmful waste chemicals that can damage the cell and lead to cell death.
2. Changes to DNA in the mitochondria
Mitochondria are unique in the cell — they have their own DNA which they use to make some of the proteins they need for energy production. This DNA is particularly susceptible to changes in its sequence during times of stress. A build-up of mutations seems to occur in the dopamine-producing brain cells in Parkinson’s, affecting energy production and putting the cell at risk.
3. Calcium overload
Dopamine-producing nerves use levels of calcium as a kind of pacemaker to enable consistent control of our movement. But this increased reliance on calcium levels likely puts further pressure on the mitochondria to manage calcium levels effectively.
4. Alpha-synuclein
We know that a protein called alpha-synuclein plays a pivotal role in Parkinson’s — it can change shape and is found in clumps in all cells affected by the condition. And recent evidence suggests that it may be a partner in crime with mitochondria.
Studies have found that alpha-synuclein can lead to extra calcium entering the cell. The protein can also be taken up by the mitochondria, where it blocks the production of energy, eventually leading to the opening of the mitochondria pore and nerve cell death.
5. Environment
We know that pesticide exposure increases the risk of developing Parkinson’s. This may be to do with the effect pesticides have on mitochondria. For example, the pesticide rotenone is known to block ATP production in mitochondria, can induce Parkinson’s-like symptoms in animal models, and has been linked to Parkinson’s in the farming community.
Past treatments
Despite the wealth of evidence we now have that mitochondria play a central role in Parkinson’s, no clinical trial of treatments targeting mitochondria has yet been found to slow or stop the condition.
The question is: why?
We spoke to Dr Heather Mortiboys, mitochondria expert and Parkinson’s UK researcher at the University of Sheffield, for answers:
“I think one of the main reasons we haven’t seen success is that tested drugs simply were not targeting the right parts of the mitochondria, or even targeting the mitochondria at all.
“Most of the compounds said to be mitochondrial protectors are actually antioxidants, which mop up the toxic waste mitochondria produce when they’re not working properly. So while they are targeting one of the side effects of dysfunctional mitochondria, they aren’t directly addressing the problem and restoring the function of the mitochondria.
“We now have more knowledge than ever before about what exactly goes wrong with mitochondria in Parkinson’s. If we’re going to have successful clinical trials, we need to be smart about how we use this information when developing drugs, making sure we’re targeting the right areas of the mitochondria to make a difference.”
Finding new targets
Parkinson’s UK is currently investing over £2 million into six different projects designed to increase our understanding of how we can best target mitochondria to slow or stop Parkinson’s progression.
This includes looking at the pores through which calcium ions get into the mitochondria, supporting mitochondria to make more energy, and finding ways to improve the recycling of damaged mitochondria from the cell.
Recycling old dysfunctional mitochondria
Professor Sylvie Urbé with Professor Michael Clague at the University of Liverpool are doing vital work to understand more about the recycling of dysfunctional mitochondria.
We know that if old mitochondria are not removed properly from the cell this can cause damage and result in the death of brain cells. This research will build on existing knowledge of recycling old mitochondria and aims to identify proteins from a list of over 400 that are involved in the tagging of old mitochondria for removal.
This research is essential in the search for new targets that could pave the way for a treatment to protect brain cells in Parkinson’s. Professor Sylvie Urbé has ongoing collaborations with Dr Heather Mortiboys. Together they are accelerating breakthroughs in research.
Drug development projects
In 2019, we invested in two new drug development projects that aim to target the energy-producing mitochondria that are affected by Parkinson’s.
By developing protective molecules that target problems with the mitochondria, the hope is to develop a safe and effective new treatment that will protect brain cells, slow the progression of Parkinson’s, and extend quality of life.
Virtual Biotech project: Developing molecules that close pores in the mitochondria
Parkinson’s UK is partnering with NRG Therapeutics Ltd to discover and develop a new medicine that protects the brain cells affected by Parkinson’s by closing pores that open when cells begin to struggle.
Project summary
In Parkinson’s, brain cells that produce dopamine are slowly lost over time. These cells are very active and require an unusually high amount of energy. They must also handle large amounts of calcium ions that continually flow into the cell when it is active, and which can become toxic.
Mitochondria can help by holding on to the calcium ions, but there’s a limit on how much they can hold. Recently, researchers have discovered that when mitochondria become overloaded with calcium, a pore in the mitochondria — known as the permeability transition pore (mPTP) — is opened. This starts the process that ultimately leads to the loss of dopamine-producing brain cells.
Using animal models of Parkinson’s, researchers have found that preventing or delaying the opening of the pores can protect brain cells and may slow the progression of the condition.
Although molecules that stop the pores opening have been known about for many years, they come from natural products and cannot easily access the brain. More recent identification of small synthetic molecules that do the same job opens up the opportunity to develop novel therapies for Parkinson’s.
The aim of this project is to develop potential drug molecules that stop the pores opening and that can also access the brain. The new drug-like molecules will then be tested to investigate if they can slow or stop the loss of cells in Parkinson’s.
If successful, this will pave the way for candidate molecules to be rapidly progressed into preclinical testing and, ultimately, clinical trials.
Virtual Biotech project: Optimising molecules that restore mitochondria
Parkinson’s UK is partnering with the University of Sheffield to design and develop a new medicine that protects the brain cells affected by Parkinson’s.
Project summary
In previous work funded by Parkinson’s UK, Dr Heather Mortiboys and her team identified compounds that have the potential to improve mitochondrial function in Parkinson’s.
By turning skin cell samples taken from people with Parkinson’s into dopamine-producing brain cells, the team was able to screen drug libraries in a relevant model, assessing which drugs could most effectively boost mitochondrial function.
They identified two compounds with excellent mitochondrial restoration properties with the potential to reduce nerve cell death. However, these compounds also have some less desirable side effects, including nausea and vomiting, making them unsuitable to progress towards clinical trials for people with Parkinson’s.
The aim of this new project is to modify these compounds so to maximise their mitochondrial boosting effects, minimise side effects and increase their suitability for use in the clinic.
The project will bring together biology and chemistry experts to design and develop a superior group of compounds that have beneficial mitochondrial restoration properties with reduced side effects. The compounds will be tested in order to find the best compound to progress along the drug discovery pipeline and ultimately into clinical trials.
The future of mitochondria and Parkinson’s
Having healthy mitochondria is essential for most cells to function properly. If we can support the health of mitochondria in Parkinson’s, we’d be on our way towards finding a treatment that stops or slows nerve cell death.
But while targeting mitochondria holds definite potential for the treatment of Parkinson’s, it may not be a cure-all for everybody.
Dr Mortiboys explains: “We can continue to identify drugs in the lab and make sure they’re optimised to be as effective as they can be. But this needs to go hand in hand with early diagnosis and clinically defining the different groups of people with Parkinson’s.
“For example, we know that problems with mitochondria are likely the cause of Parkinson’s in people with changes in the PINK1 or Parkin genes, but for others, problems with the alpha-synuclein protein may come first, which then impact on the mitochondria. It’s likely that the different groups will need different treatments or a combination of treatments.”
Such personalised medicine is gaining momentum as the way forward for medical research, and in the case of mitochondria and Parkinson’s, may well provide the cure.
