The science behind Parkinson’s
Our understanding of Parkinson’s is increasing all the time and new discoveries about the science behind the condition are taking us closer to finding treatments that can slow, stop or even reverse the progression of the disease.
Cure Parkinson’s is working tirelessly with major efforts being directed at key biochemical pathways that have been revealed; and thanks to our supporters, we’re funding some of the most pioneering and promising work in these areas.
Here we give a summary of what we now know about the science behind Parkinson’s, and outline our current major research areas.
What do we know about the possible 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. 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 clear cut; we know that not everyone who carries one of these causal Parkinson’s gene variations will go on to develop the condition, so other factors must also be involved.
There is a lot of evidence to show that sustained exposure to certain environmental risks can cause Parkinson’s. Exposure to certain pesticides, such as paraquat, have been associated with an increased risk of developing Parkinson’s, and many such toxic chemicals are now banned in some countries. Recently, the chemical trichloroethylene, which has been widely used in industrial cleaning products, has been reported to be associated with the development of Parkinson’s.
Traumatic brain injury (TBI) is another environmental factor that has been linked to an increased risk of developing Parkinson’s. TBI is increasingly being discussed as a trigger for a range of neurological disorders with the media focusing on rugby, football and boxing sportspeople who have been diagnosed with neurodegenerative conditions.
A 2018 paper in the journal Neurology showed that TBI is associated with an increased risk of Parkinson’s. Researchers revealed that mild TBI (defined as loss of consciousness for less than 30 minutes and memory loss for less than 24 hours) increased the risk of Parkinson’s by 56 percent whereas moderate to severe TBI (defined as loss of consciousness for more than 30 minutes and memory loss for more than 24 hours) increased the Parkinson’s risk by 83 percent.
In a study published at the 2021 Alzheimers Association International Conference and later published in Alzheimers & Dementia in 2022, evidence suggested that TBI is associated with an earlier age of Parkinson’s onset, but not with more severe disease-associated nerve cell loss or younger age of death.
Longitudinal and epidemiology studies have shown that there is an increased risk of Parkinson’s associated with consumption of dairy products, history of melanoma, and TBI.
These same studies have reported a reduced risk in association with smoking, caffeine consumption, higher serum urate concentrations, physical activity, and use of ibuprofen and other common medications.
Further reading:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957305/
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.051517
https://www.sciencedirect.com/science/article/abs/pii/S1474442216302307
https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd225047
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 from person to person. However, everyone with Parkinson’s has something in common: they have all lost a large proportion of the dopamine-producing neurons (or nerve cells) in their brain. These neurons sit deep inside the brain, each one extending a vast network of branches into the overlying brain tissue – called the striatum – where they release dopamine. This dopamine release is vital to 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-producing neurons that lead to Parkinson’s can occur due to a number of faulty biological processes which damage and stress them. We don’t yet understand which of these stresses come first, and which are the most impactful. 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 neuron 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. The 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 targets to slow, stop or reverse Parkinson’s:
Mitochondrial dysfunction
Mitochondria are like ‘battery packs’ inside our cells. Dopamine producing nerve cells (or neurons) in the brain 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 of energy and lead to their 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 compounds that have the potential to restore vital mitochondrial function, enhancing energy production in dopamine neurons. One such clinical trial is looking to repurpose UDCA, a treatment for liver disease, targeting mitochondrial dysfunction in Parkinson’s.
UDCA and Parkinson’s
Waste removal
In Parkinson’s, the neurons’ normal processes for discarding waste may be faulty allowing substances to build up and become toxic, such as the protein alpha-synuclein. Methods of restoring the proper biological waste disposal pathways in cells are currently of great research interest. GCase is an enzyme that helps to break down proteins ready for proper cellular disposal. GCase is encoded by a region of DNA called the GBA-1 gene. However, around 10% of people with Parkinson’s carry a fault in this GBA-1 gene, and it is thought this is the cause of their Parkinson’s. Cure Parkinson’s has funded a successful phase 2 clinical trial of a drug called ambroxol, which is thought to increase levels of GCase in cells, thereby improving proper cellular waste disposal. We are now looking to drive this research towards the next phase of clinical development.
Ambroxol and Parkinson’s
Alpha-synuclein accumulation
Alpha-synuclein is a protein which is abundant in dopamine producing nerve cells; it is especially concentrated in the brain, while smaller amounts are found in the heart, muscle and other tissues. In Parkinson’s however, alpha-synuclein mis-folds and aggregates into clumps called Lewy Bodies. It’s thought these may be toxic and the clumps of alpha-synuclein get passed from one neuron to another, possibly causing the spread of the disease through the brain. Cure Parkinson’s is supporting research and clinical trials which are targeting alpha-synuclein aggregation – the Anle138b clinical trial is one such trial.
Anle138b 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 a toxic form of the protein alpha-synuclein. Chronic low-level inflammation in Parkinson’s is aided by a complex of proteins known as the inflammasome. Researchers have proposed reducing inflammation in Parkinson’s as a means of potentially slowing the progression of the condition. Cure Parkinson’s is currently supporting a phase 2 clinical study in Cambridge evaluating the anti-inflammatory drug azathioprine.
Azathioprine and Parkinson’s
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 molecules are believed to be a source of oxidative stress in dopamine neurons. Iron chelating (removal) medicines, which are used to treat people with certain blood disorders, are also being studied as potential treatments for Parkinson’s.
Iron chelation and Parkinson’sOther important research areas
As previously discussed, no two cases of Parkinson’s are the same and as a result, the treatment needs of each individual will be different. This is termed a multi-modal approach.
Looking ahead, once a drug or a treatment has been determined to stop or slow the progression of Parkinson’s, neurons will require ‘neuroprotection’ and this is another important area of Parkinson’s research. Other strategies aim to nourish and protect dopamine neurons by introducing neurotrophic factors.
Of further research interest is dopamine cell replacement therapy, which seeks to introduce healthy functioning dopamine neurons deep into the brain to replace those neurons lost to the disease.
Neuroprotection
Exenatide is a Glucagon like peptide-1 receptor (or GLP-1R) agonist. This is a class of drug that has traditionally been used for treating diabetes, but has recently been repurposed in a clinical trial for Parkinson’s after multiple studies suggested neuroprotective effects in laboratory models of Parkinson’s. A number of research studies have been developed to test diabetes medicines in Parkinson’s.
Diabetes and Parkinson’s
Nerve growth (neurotrophic) factors
Another area of neuroprotection is that of nerve growth (or neurotrophic) factors. These are supportive nurturing proteins that the brain produces naturally and they play important roles in both the development of neurons and neuron survival. There are many types of neurotrophic factors which support different neurons in a variety of ways.
Nerve growth factors for Parkinson’s
Neuron replacement (or cell-replacement) therapy
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 people with Parkinson’s. Other trials are underway around the world using dopamine neurons grown from stem cells.
Cell replacement therapy for Parkinson’sPrecision medicine
PD FRONTLINE
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 sub-types of Parkinson’s.
Find out more
The sub-types of Parkinson’s
This is 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 offers genetic testing for people with Parkinson’s to help people understand their condition a little more, and build clinically ‘trial-ready’ groups of people whose Parkinson’s is likely to have similar underlying biochemistry.
Elsewhere, several research groups are testing immunotherapies (or vaccines) against the Parkinson’s hallmark protein alpha-synuclein. 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.
