Exploring the Causes of Parkinson’s Disease: Genetics, Environment, and Levy Bodies

Parkinson’s disease is one of the most common neurodegenerative disorders in the world, and yet its causes remain one of medicine’s most complex puzzles. According to the National Institute of Neurological Disorders and Stroke, Parkinson’s disease is a progressive movement disorder that causes nerve cells in parts of the brain to weaken, become damaged, and ultimately die. Most people associate it with tremors, but the disease affects far more than movement – it can alter mood, cognition, sleep, and autonomic function. What drives this slow destruction of brain cells? The answer isn’t simple. Research consistently points to an intricate interplay of genetics, environmental exposures, and abnormal protein behaviour within the brain. Understanding these causes is not just an academic exercise – it lays the foundation for better prevention strategies, earlier diagnosis, and, one day, a cure.

No single cause: understanding Parkinson’s as a multifactorial disease 🔗

Parkinson’s disease has no single cause; rather, genetic and environmental factors interact and affect critical cellular processes in a complex interplay. The disease centrally involves the gradual degeneration of dopamine-producing neurons in a brain region called the substantia nigra. Dopamine is the chemical messenger that enables smooth, purposeful movement. Studies show that most people with Parkinson’s have lost 60 to 80% or more of their dopamine-producing cells in this region by the time symptoms actually appear – which means the disease progresses silently for years before it becomes clinically visible. This delayed onset makes identifying definitive causes particularly challenging for researchers.

Genetic predisposition and family history 🔗

Genetics plays a meaningful but not deterministic role in Parkinson’s disease. About 15% of people with Parkinson’s have a family history of the condition, and family-linked cases can result from mutations in a specific group of genes, including LRRK2, PARK2, PARK7, PINK1, and the SNCA gene. The heritability of the disease, estimated from both twin studies and statistical genetic methods, lies somewhere between 22% and 40%, suggesting that genetic contributions are real but rarely operate alone.

Key genes and what they do 🔗

Mutations in six genes – SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2 – have conclusively been shown to cause familial parkinsonism. Each of these genes plays a role in fundamental cellular functions. The SNCA gene, for instance, produces a protein called alpha-synuclein, which in its normal form supports synaptic function. When this gene mutates or is overexpressed, the protein misfolds and accumulates harmfully. The PARK2 gene produces a protein called parkin, which normally helps cells break down and recycle damaged proteins. When parkin function is disrupted, proteins accumulate and become toxic to neurons. Similarly, mutations in PINK1 impair mitochondrial function – the energy factories of cells – making neurons far more vulnerable to stress and degeneration.

It is important to note that carrying one of these genetic mutations does not guarantee developing Parkinson’s disease. Most people who carry these genetic risk factors will not go on to develop the disease. The genetic landscape of Parkinson’s is better understood as raising susceptibility rather than sealing fate. This is where environment enters the picture.

Environmental risk factors 🔗

Environmental exposures are considered a major contributor to Parkinson’s disease, and the evidence linking specific toxins to the disease has grown substantially over recent decades. Epidemiological studies have found increased risk of Parkinson’s disease associated with exposure to environmental toxicants such as pesticides, solvents, metals, and other pollutants – and many of these compounds reproduce Parkinson’s-like pathology in animal models.

Pesticides and herbicides 🔗

The link between agricultural chemicals and Parkinson’s is among the most studied. A strong link has been shown between Parkinson’s disease and exposure to pesticides and herbicides, particularly chemicals like paraquat, rotenone, and organochlorines. The herbicide paraquat has attracted particular attention – research has linked exposure to paraquat with a 150% increased risk of developing Parkinson’s disease, and it has already been banned in over 30 countries due to its associations with neurological disease. Farm workers and agricultural labourers have a substantially elevated risk, as their occupational exposure to these chemicals is chronic and often begins in mid-life – the very period that may be most consequential for later neurodegeneration.

The biological mechanism is also becoming clearer. Studies suggest that certain pesticides can induce a conformational change in alpha-synuclein and accelerate the formation of alpha-synuclein fibrils – the abnormal protein clusters that damage brain cells. In other words, pesticide exposure doesn’t just increase statistical risk; it may actively accelerate the very molecular process that defines Parkinson’s pathology.

Heavy metals and industrial solvents 🔗

Beyond pesticides, other industrial substances also raise concern. High-dose manganese exposure, linked to occupations such as welding, is known to cause a form of parkinsonism called manganism, and exposure to lead has also been associated with a greater risk of developing Parkinson’s. Industrial solvents present another risk vector. Trichloroethylene (TCE) – used in metal degreasing, dry cleaning, and manufacturing – has been associated with a dramatically elevated risk. Researchers have linked TCE exposure with a 500% increased risk of Parkinson’s disease, and because TCE has contaminated groundwater across many regions, the exposure is far more widespread than most people realise.

A growing body of evidence suggests that exposure to pesticides, solvents, heavy metals, microplastics, and air pollution is at least in part responsible for the rapid growth in Parkinson’s disease prevalence over recent decades. Research also suggests that chronic, low-level exposure over many years may be just as damaging as more concentrated events with a shorter exposure window – making regulatory action on environmental chemicals a public health priority, not just a scientific concern.

The interaction between genes and environment 🔗

Genes and environment do not operate in separate silos. Some people inherit genetic variants – such as those in the GBA1 or LRRK2 genes – that make neurons more vulnerable to stress and toxins. When these individuals are exposed to pesticides, the combined effect can dramatically increase their lifetime Parkinson’s risk. This gene-environment interaction helps explain why two people with identical toxic exposures can have very different outcomes – one’s underlying genetic makeup may simply render their neurons less resilient to the same chemical insult.

The role of Lewy bodies 🔗

At the cellular level, one of the most defining features of Parkinson’s disease is the presence of abnormal protein deposits inside neurons called Lewy bodies. The pathological hallmark of Parkinson’s disease is the presence of abnormal cytoplasmic deposits within neuronal cell bodies that are immunoreactive for the protein alpha-synuclein. These deposits, named after neurologist Frederic Lewy who first described microscopic particles in affected brains in 1912, are now understood to be central to the disease’s progression.

What is alpha-synuclein and why does it matter? 🔗

Alpha-synuclein is a protein predominantly found in the presynaptic terminals of neurons, where it plays a normal role in regulating synaptic vesicle trafficking, neurotransmitter release, and vesicle recycling. Alpha-synuclein can become problematic when misfolding and aggregation take place, leading to oligomers and fibrils that can form Lewy bodies associated with neurodegenerative disease.

In a healthy brain, the cell’s protein disposal systems – including the ubiquitin-proteasome system and autophagy pathways – clear away misfolded proteins before they accumulate. In Parkinson’s disease, this clearance system appears to fail. Some research suggests that the cell’s protein disposal system may fail in people with Parkinson’s, causing proteins to build up to harmful levels and trigger cell death. Once alpha-synuclein begins to misfold, it forms small toxic clusters called oligomers, which then aggregate into larger insoluble fibrils, and eventually compact into the larger structures visible as Lewy bodies.

How Lewy bodies damage the brain 🔗

Abnormal forms of alpha-synuclein trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis – a cascade of cellular failures that ultimately kills dopamine-producing neurons. Research published in the Proceedings of the National Academy of Sciences found that the process of Lewy body formation is one of the major drivers of neurodegeneration, disrupting cellular functions and inducing mitochondria damage and synaptic dysfunction.

Research has also shown that alpha-synuclein pathology can spread progressively through the brain, moving from cell to cell over time. The latest scientific thinking is that alpha-synuclein transfers from cell to cell – researchers have identified a protein that allows clumps of alpha-synuclein to enter cells, and therapies that could interfere with this process are now being explored. This propagation model helps explain why Parkinson’s symptoms worsen over time even when the initial trigger may be limited to a specific brain region.

It is worth noting that Lewy bodies are not exclusively found in Parkinson’s disease. They also appear in related conditions such as dementia with Lewy bodies and multiple system atrophy. Some Parkinson’s disease cases lack Lewy bodies entirely, and other brain pathologies also play important roles – a reminder that Parkinson’s is likely better understood as a heterogeneous syndrome rather than a single, uniform disease.

What all three causes have in common 🔗

Whether the trigger is a genetic mutation, a toxic chemical, or a misfiring protein, the end result in Parkinson’s disease is the same: the death of dopamine-producing neurons in the substantia nigra, leading to the motor symptoms the condition is known for. What makes this disease so difficult to study – and to treat – is that these three pathways are deeply interconnected. Toxins such as those that impair mitochondrial function can lead to an increase in reactive oxygen species in neurons, which in turn elevates alpha-synuclein oligomerization, creating a vicious cycle of death for dopaminergic neurons. Genetics, meanwhile, can lower the threshold at which these toxic cascades are triggered.

Understanding the causes of Parkinson’s disease is not merely an academic pursuit. It drives research into early biomarkers that could detect the disease before symptoms emerge, informs policy decisions about environmental regulation of harmful chemicals, and opens new targets for therapies that go beyond managing symptoms to actually slowing or halting the disease’s progression. As research into genetic testing, alpha-synuclein inhibition, and environmental risk reduction accelerates, there is growing optimism that what is today a managed condition could, in the future, become a preventable one.

What do you think? Given that both genetics and environment contribute to Parkinson’s disease, where should public health efforts be focused first – on genetic screening for at-risk individuals or on stricter regulation of environmental toxins like pesticides and industrial solvents? And if the cell’s protein disposal system plays a key role in allowing alpha-synuclein to accumulate, could future therapies targeting that system change how we treat Parkinson’s disease entirely?

References

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