The science behind Parkinson's

Our understanding of Parkinson’s is increasing all the time. Every month, more scientific findings add to the evidence, and take us one step closer to a cure

We are working tirelessly to find a cure. Major efforts are being directed at several of the key biochemical pathways and events that have been revealed by Parkinson’s research, and thanks to our supporters, we’re funding some of the most promising areas.

Here we give a summary of what we now know about the science behind Parkinson’s, and outline our major current areas of progress in the global Parkinson’s research arena.

The causes of Parkinson’s

In most people with Parkinson’s, the condition is described as ‘idiopathic’. This means that we don’t know the exact cause. However, we do know that genetic and environmental factors often play a role.

Research has shown that people who carry small variations in one of over 20 genes, are more likely to develop Parkinson’s. That’s why the condition can run in families. However, it’s not black and white. Not everyone who carries one of these pro-Parkinson’s variations will go on to develop the condition, so other factors must be at play.

There is a lot of evidence to show that sustained exposure to certain pesticides, such as paraquat, can cause Parkinson’s. Many of these toxic chemicals are now banned in some countries.

The biochemistry of Parkinson’s

The underlying biochemistry going on inside the brains of people with Parkinson’s seems to be quite variable. The impact of this is that some people experience symptoms that others do not, some respond better to certain treatment, and the rate of progression varies.

However, everyone with Parkinson’s has something in common: they have all lost a large proportion of the dopamine neurons in their brain. These neurons sit deep inside the brain, each one extending a copious network of branches into the overlying brain tissue – called the striatum – where they release dopamine. This dopamine release is vital for allowing the flow of messages from our brain to our skeletal muscles. Without it, we struggle to initiate and control movement of our limbs, creating the rigidity and tremor evident in Parkinson’s.

In Parkinson’s why do dopamine neurons die?

Research suggests that the death of dopamine neurons that leads to Parkinson’s can occur due to a number of faulty processes which damage and stress the cells. We don’t yet understand which of these stresses come first, and which are the most important. However, it’s likely that there is an interplay between some or all of the factors discussed in this section which create a vicious cycle that leads to cell death.

Parkinson’s is currently treated with medications that boost the levels of dopamine in the brain. The most common of these treatments is called levodopa. These medications temporarily remove the symptoms of the condition, allowing people to live relatively normal lives however, over time, these therapies lose their potency as the underlying condition continues to progress.

We urgently need a cure for Parkinson’s – a treatment that will slow, stop or reverse the loss of dopamine neurons.

Finding a cure – our major research areas

Alpha-synuclein accumulation

Alpha-synuclein is a protein abundant in dopamine neurons. In Parkinson’s however, it misfolds and aggregates into clumps called Lewy Bodies. It’s thought these may be toxic and the aggregates of alpha-synuclein may also get passed from one neuron to its neighbour, causing the spread of the disease through the brain.

In laboratory conditions and in animals, nortriptyline has been shown to prevent the accumulation of alpha-synuclein in neurons. Cure Parkinson’s is currently supporting a UK-based clinical trial of the anti-depressant drugs nortriptyline and escitalopram in Parkinson’s.

Nortriptyline and Parkinson’s

Elsewhere, several research groups are testing immunotherapies (or vaccines) against the Parkinson’s hallmark protein. Immunotherapy is a method of directing our immune system to mount defences against specific pathogens or rogue proteins such as the mis-folded alpha-synuclein protein which is a common biological feature of Parkinson’s. Clinical trials of potential vaccines against alpha-synuclein are underway.

The Affiris Trial The Prothena Trial

Mitochondrial dysfunction

Mitochondria are the power stations inside our cells. Dopamine neurons are cellular ‘gas guzzlers’ – they need a lot of energy to do their job – but mitochondria don’t seem to function well in Parkinson’s, which may starve the neurons to death. Mitochondria are also involved in triggering cell self-destruction, which may be another cause of neuron loss in Parkinson’s.

Through our International Linked Clinical Trials programme (iLCT), Cure Parkinson’s has prioritised two compounds that have the potential to restore vital mitochondrial function, enhancing energy production in dopamine neurons. A small safety study of EPI-589 has so far been completed, and a Phase II clinical trial is underway looking to repurpose UDCA – a treatment for liver disease – in targeting mitochondrial dysfunction in Parkinson’s.

UCDA and Parkinson’s

Inflammation

In Parkinson’s – as with many long-term illnesses – we find chronic inflammation in tissues. Inflammation is an important part of our bodies’ immune defences, but when it is sustained it can cause many damaging effects. In Parkinson’s, inflammation in the brain may contribute to over-production of alpha-synuclein.

Chronic low-level inflammation in Parkinson’s is aided by a complex of proteins known as the inflammasome. A phase 1 trial of a small molecule that inhibits the inflammasome has shown positive results, and we look forward to seeing a phase 2 trial start very soon.

Cure Parkinson’s has been at the forefront of research into exenatide, a diabetes medicine shown to have potential as a disease-modifier in Parkinson’s. Exenatide’s beneficial effects seem to stem partly from dampening down inflammation.

Exenatide and Parkinson’s

Waste removal

In Parkinson’s, the neurons’ normal processes for discarding waste may be faulty, so toxic substances can build up – including clumping alpha-synuclein. Up to 10% of people with Parkinson’s carry a fault in the GBA-1 gene, which is involved in cellular waste removal.

Restoring the activity of a waste-removal enzyme called GCase is of great current research interest. GCase is an enzyme that breaks down proteins ready for disposal. It is coded by the GBA-1 gene, mutations in which are found in many people with Parkinson’s.

Cure Parkinson’s funded a successful phase 2 clinical trial of ambroxol, which is thought to boost GCase activity, and we’re now looking to drive this research towards the next phase of clinical development.

Ambroxol and Parkinson’s

Elsewhere, a biotech company is running a gene therapy trial to introduce a functional version of the GBA-1 gene into the brains of people with Parkinson’s who carry the GBA-1 mutation.

The Prevail Trial

Oxidative stress

Mitochondrial dysfunction also contributes to high levels of very volatile molecules (known as reactive oxygen species) found within dopamine neurons in Parkinson’s. These react with, and damage, their surroundings. They may also contribute to the aggregation of alpha-synuclein.

High levels of free and reactive iron are believed to be a source of oxidative stress in dopamine neurons. Iron chelation (removal) medicine which is already used in people with certain blood disorders, is also being studies in Parkinson’s.

Iron chelation and Parkinson’s

Neuron survival and replacement

In addition to research targeted at the biochemical pathways involved in Parkinson’s, there are also exciting ‘wholesale’ approaches underway.

Some of these strategies aim to nourish and protect dopamine neurons by introducing neurotrophic factors. A clinical study in Bristol has investigated the neuroprotective protein GDNF, which was co-funded by Cure Parkinson’s.

Another avenue of great interest is cell replacement therapy; introducing functional healthy dopamine neurons deep into the brain. Cure Parkinson’s is supporting TRANSEURO, a Europe-wide trial testing dopamine cell replacement therapies with foetal-derived dopamine neurons in 13 people with Parkinson’s. Other trials are underway around the world using dopamine neurons grown from stem cells.

The GDNF Trial Dopamine cell replacement therapies

Precision medicine

As research reveals the complex biology that underlies Parkinson’s, it’s clear that a ‘one size fits all’ approach to curing the condition is unlikely to be successful. That’s why there’s increasing care to develop therapies and design clinical trials towards subtypes of Parkinson’s. It’s called ‘stratification’, and one way to stratify people with Parkinson’s is according to gene variations that may have contributed to their disease. For instance, those with mutations in the GBA-1 gene may benefit the most from therapies aimed at boosting cellular waste disposal.

The PD Frontline study is offering genetic testing for people with Parkinson’s. This will help people to understand their condition a little more, and will begin to build clinical trial-ready groups of people whose Parkinson’s is likely to have similar underlying biochemistry.

PD Frontline

Progress and promise

Insights from over 200 years of research have led to treatments that now help to give people with Parkinson’s around the world, a better quality of life.

Our goal is to find a cure, as quickly as possible. We’ll get there by untangling exactly why people develop Parkinson’s, and the biochemistry that underlies its progression.

When Cure Parkinson’s began in 2005, many people thought that our goal was unrealistic. Since then, research has progressed enormously revealing much more about the science behind Parkinson’s presenting new targets that could be hit to interrupt the course of the disease.

Today, people no longer think our quest for a cure is unrealistic – it’s just a matter of time.

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