Our understanding of Parkinson’s is increasing all the time and new discoveries about the science behind the condition are bringing us closer to finding treatments that can slow, stop or even reverse the progression of Parkinson’s.

What is Parkinson’s?

Parkinson’s is characterised by the progressive loss of nerve cells (neurons) in part of the brain called the substantia nigra, which helps the body control movement. These neurons produce an important molecule called dopamine, which helps them to communicate with one another. Without adequate dopamine levels, neurons are unable to signal and coordinate movement properly, leading to the motor symptoms we commonly see in Parkinson’s.

As Parkinson’s progresses, it can affect other areas of the brain as well, leading to a wide range of nonmotor symptoms. Typically, at the time of diagnosis, people with Parkinson’s have already lost around 60% of these dopamine-producing neurons. Therefore, to alter progression of the condition, Cure Parkinson’s is

interested in finding therapies that target the underlying biology that is driving neuron loss in Parkinson’s, with the hope to slow, stop, or reverse progression.

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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 complex role. Research has shown that people who carry small variations in one of over 20 genes, are more likely to develop Parkinson’s. However, it’s not clear cut; we know that not everyone who carries one of these genetic variations will go on to develop the condition, so other factors must also be involved.

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There is evidence to show that sustained exposure to certain environmental factors 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 athletes 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%, whereas moderate to severe TBI (defined as loss of consciousness for more than 30 minutes and memory loss for more than 24 hours) increased Parkinson’s risk by 83%.

In a study published at the 2021 Alzheimer’s Association International Conference, and later in Alzheimer’s & Dementia in 2022, evidence suggested that TBI was 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, and physical activity.

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What do we mean by therapy target?

Therapy targets refer to the underlying biological mechanisms that we believe play a role in driving the development and progression of Parkinson’s. By finding drugs that can address these targets, we may be able to slow, stop, or reverse Parkinson’s progression.

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Finding a cure – our major research targets to slow, stop or reverse Parkinson’s:

Alpha-synuclein accumulation

Alpha-synuclein is a protein most abundantly found in neurons. In Parkinson’s, however, neurons begin producing dysfunctional copies of alpha-synuclein, which build-up and aggregate into clumps called Lewy bodies. These bodies interfere with the cell’s ability to function normally, eventually leading to cell loss if not cleared. Furthermore, researchers believe these clumps can pass from one neuron to another, possibly contributing to the spread of Parkinson’s throughout the brain. The presence of alpha-synuclein and Lewy bodies is considered a hallmark and driver of Parkinson’s and there is extensive research into compounds with the potential to breakdown or prevent the formation of Lewy bodies, consequently altering progression of the condition.

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Waste removal

An important aspect for maintaining the health of a cell is the breakdown and recycling of waste, including excess proteins and dysfunctional structures. In Parkinson’s, the neuron’s normal processes for discarding waste may be faulty, allowing substances to build-up and become toxic, such as the protein alpha-synuclein. Researchers are interested in whether improving waste clearance in neurons could help to protect or rescue them, slowing Parkinson’s progression.

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Neuroinflammation

Inflammation is an important part of our bodies’ immune defences, but when it is sustained, it can lead to the damage of normal, healthy cells. There are several pathways thought to be implicated in promoting neuroinflammation (inflammation in the brain) in Parkinson’s, including overproduction of pro-inflammatory molecules called inflammasomes, overactivation of specialised immune cells in the brain, and even whether chronic inflammation elsewhere in the body (such as the gut) could initiate neuroinflammation. Researchers are now looking to see whether reducing neuroinflammation in Parkinson’s could potentially slow the progression of the condition.

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Mitochondrial dysfunction

Mitochondria are like “battery packs” inside our cells, producing most of the energy that they need to function. As we all age, our mitochondria become less efficient; however, in Parkinson’s this reduction in efficiency is exaggerated. Neurons may become starved of energy, eventually leading to their death. Mitochondria are also involved in triggering several cell-death pathways, which may be another driver of neuron loss. Researchers are investigating if therapies that can rescue neuronal energy production could help slow Parkinson’s progression.

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Oxidative stress

Mitochondrial dysfunction is also thought to contribute to high levels of toxic molecules (called reactive oxygen species), which react with and damage their surroundings. If cells are unable to clear the build-up of these molecules, they can cause “oxidative stress”, preventing cells from functioning properly and eventually triggering cell death. In Parkinson’s, oxidative stress is thought to contribute to neuron loss. Therefore, researchers are interested in whether therapies that can mitigate oxidative stress could prevent Parkinson’s progression.

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Other 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, or personalised, approach. 

Looking ahead, once a drug or 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.

Neuroprotection

Neuroprotection refers generally to the ability of therapies to prevent neuron death. Therapies that fall in this category may be targeting a feature of Parkinson’s that is not included in our five therapy targets, may have an unknown mechanism of action, or may be acting on multiple targets. One class of drugs that is of particular interest for this area are GLP-1 receptor agonists, a Type 2 diabetes medication.

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Nerve growth (neurotrophic) factors

Nerve growth factors, also called neurotrophic factors, are proteins that support neurons by encouraging their growth, development, and survival. Researchers believe increasing levels of these factors may help prevent dopamine neuron loss by protecting and restoring neurons, thus slowing Parkinson’s progression. Several neurotrophic factors associated with dopamine-producing neurons are currently being researched pre-clinically and in trials around the globe to determine whether they could restore neuron function.

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Cell-replacement therapy

Unlike body cells, our neurons are not regularly replaced throughout our lifetime; for the most part, neurogenesis, or the growth of new neurons, ceases after childhood. This is why Parkinson’s is a progressive condition; the dopamine neurons that are lost as the condition progresses are not replaced. Therefore, researchers are interested in using cell-replacement therapy to introduce functional, healthy dopamine neurons deep into the brain.

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