Genetic And Environmental Causes Of Parkinson's Disease
The direct cause of Parkinson’s disease is not yet known. Scientists have accumulated a pool of potential risk factors – lifestyle and environmental – to decipher this mysterious neurodegenerative disorder. Genetics and factors like age, gender, pesticide and metal exposure, and head injuries seem to play a cooperative role in bringing about PD. Interestingly, gut bacteria may have something to do with PD as well.
You reach out for your knife and fork to slice the steak on your plate, something you learned as a child and have been doing successfully for several decades in a row. To your utter surprise, what seemed to be a part of your muscle memory by now becomes a conscious effort, a struggle. Your hands quiver and you wonder what on earth is going on. This could happen to anyone. Absolutely anyone.
Researchers agree that Parkinson’s disease is caused by both genetic and environmental factors. The interaction between your genetic makeup and your lifestyle and surroundings will determine whether you will ever develop Parkinson’s disease or not.
What Is Parkinson’s Disease?
Parkinson’s disease (PD) is a motor system disorder resulting from the loss of dopamine-producing cells in the brain.1 PD mostly affects people over 60 years of age, but in rare cases can start as early as your 20s. The rate at which it progresses is different for different people, and early symptoms are difficult to catch.
PD affects your movements in a way that you cannot control it. It starts out with tremors, stiffness, and slow movements and gradually progresses into difficulty swallowing, speaking, sleeping, and even thinking. The most unfortunate part is that daily activities that you’ve been doing for years become not so doable, affecting relationships and your basic quality of life.
Causes Of Parkinson’s Disease
Dopamine, a neurotransmitter produced by nerve cells in the substantia nigra (midbrain), coordinates muscle movement.2 3 When small clusters of dopamine-producing cells die, at least half of them, body movements become visibly impaired.4 This is how PD is caused at the molecular level. What triggers this kind of nerve degeneration is still being extensively researched.
So, what we must understand is that no one really knows the cause for Parkinson’s yet. Scientists have made good progress toward finding out what it can be, but right now they are stuck in a pool of risk factors and contributing factors rather than a direct cause.
Most cases of PD are due to a combination of the following factors:
The feeling of not knowing whether you or a loved one is at a risk for Parkinson’s can be frighteningly unnerving. Knowing that a grandparent had PD or a sibling has it leaves plenty of room for suspicion about who else could have it, including yourself.
Only 30% of the familial and 3%–5% of the sporadic cases of PD can be attributed to single gene mutations.5
Most studies on Parkinson’s have been genetic studies because of the ease and convenience with which they can be performed in a laboratory. However, only rare cases of PD are caused only due to genetic reasons.
By studying generations of families with a history of Parkinson’s, visible genetic similarities have been seen – multiple copies of a single gene or mutations in a gene.6 But here’s the stumbling block. While two people may have had the same genetic problems, they did not contract the disease at the same age and their experiences of it, in terms of symptoms, were often very different from each other. Also, if two individuals had a mutation in the same gene, the kind of mutation was often varied.
The following types of genes play a role in PD:
1. Causal Genes
Multiple copies of the PARK 1 gene have been linked to early-onset Parkinson’s. The product of this gene, alpha-synuclein, has been seen to damage nerve cells in the brain.
A causal gene is a gene which, if inherited, can cause a disease on its own, without any other influencing factor like the environment. A meager 1% to 2% of people suffering from PD develop the disease because of a causal gene.
- Alpha-synuclein (PARK 1 gene): This gene is mostly associated with early-onset PD – that is, in individuals less than 50 years of age.7 However, most researchers believe that no matter what the cause for PD, all genetic and cellular changes linked with PD eventually cause the overexpression and accumulation of the product of this gene – the protein alpha-synuclein.8
Alpha-synuclein can be overexpressed when multiple copies of its gene exist as opposed to only one copy in a normal individual. A famous study on the Iowa family brought to light 3 copies of this gene in members who suffered from PD. Alpha-synuclein damages the cell membranes of dopamine-producing neurons in the brain leading to their death. This protein has been found in Lewy bodies, abnormal protein clusters in the brain that are a risk factor for PD.
2. Associated Genes
Even if you don’t have a causal gene, you may have associated genes that add fuel to fire caused by other environmental factors that may actually trigger PD.
Unlike a causal gene, an associated gene cannot cause PD on its own. It can only increase the risk of the disease. This means that a person carrying an associated gene is more susceptible to PD than others but may not develop PD at all.
- Dardarin (LRRK2 or PARK8 gene): Mutations in the gene coding the protein dardarin are most common in people of North African, Basque, Portuguese, and Ashkenazi Jewish descent, but can be seen across all ethnicities. PD caused by mutations in this gene usually shows mid-to-late onset and slow progression.
Besides alpha-synuclein and dardarin, there are a host of other causal and associated genes that play a role in PD.
Environmental And Other Factors
Scientists have been meticulously scanning through non-genetic factors that influence PD risk. Putting yourself in their shoes, you may understand how challenging this must be with the numerous possibilities. But what can come out of this endeavor has magnificent potential in the intervention and prevention of PD.
Most cases of PD are sporadic and not genetic. Often, lifestyle and environmental factors stave off the onset of PD in individuals who are genetically predisposed to it.
The following are the most prominent factors:
PD usually starts showing up around 60, and most patients are above 85.
Parkinson’s disease is the second most common age-related neurodegenerative disorder after Alzheimer’s.9 Over 1% of the population over the age of 60 and 5% over 85 suffer from PD. Only a small 5% of PD cases advance before 60 years of age and are linked to gene mutations.
With advancing age, the neurons in the substantia nigra (SN) are faced with an entourage of stressors – such as free radicals from dopamine metabolism and a dearth of cellular energy. Together, these make the SN neurons more vulnerable to degeneration than other parts of the brain.
Parkinson’s is 1.5 to 2 times more common in men than women.
More men have been diagnosed with PD than women.10 It is not yet known whether hormones, genes, or lifestyles are the determinants of this gender disparity. Women are also seen to have less severe symptoms than men, and an approximately 2 year later onset of the disease.
3. Toxin Exposure
Studies have suggested that pesticides, industrial compounds, and metals may contribute to PD.11 This means that people working in close proximity to farmland (like farmers), who live near farmland and near wells (rural occupants), and those whose jobs require regular exposure to metals (welders) are at a higher risk of PD.
Pesticides: Strong evidence exists implicating the pesticides rotenone, paraquat, maneb, and organochlorines in PD. Organophosphates and pyrethroids, on the other hand, have limited but suggestive data linked with PD. Pyrethroids are a newer class of insecticides, common in household insecticides and mosquito repellents.
Most people who are exposed to pesticides do not develop PD. Those who do usually also have a gene mutation that affects dopamine transport.
- Organochlorines (e.g., DDT used to kill mosquitoes and dieldrin for termites) were extensively used as pesticides in the U.S. in the 1940s-70s. Though they have been banned for some time now, their chemical structure resists degradation and may remain in the soil and food chain for a long time.12 This means they continue to be a neurotoxic threat.
- Studies showed that people who used rotenone (a plant-derived insecticide often used to kill fish in reservoirs) or paraquat (herbicide) developed PD 2.5 times more often than non-users.13 Rotenone obstructs energy production in the cell, while paraquat produces damaging free radicals in the cell.
Metals: High levels of iron have been found in the brains of patients with PD. However, the link between iron and PD is still not established. Manganese has been a subject of keen interest in PD studies; however, there are only a few supportive studies.
4. Head Trauma
Traumatic head injury is a potential risk factor of PD, but the risks are probably higher when you already have high levels of the protein alpha-synuclein.
An individual who has suffered a traumatic head injury, one that causes loss of memory or consciousness, is at a higher risk of developing PD than others.14 It is hypothesized that such injuries cause PD by increasing alpha-synuclein levels and by eliciting inflammation in the brain.15
One study suggests that head injuries can only increase risks of PD in individuals who already have abnormally high levels of alpha-synuclein.16
The Link Between Alcohol And Parkinson’s Is Not Yet Established
The interest in whether alcohol is linked in any way to PD stems from previous studies linking caffeine and smoking to PD. While studies show that caffeine drinkers and smokers are at a reduced risk of PD, 2 studies found an increased risk of PD with alcohol consumption.17 However, there has been contradictory evidence as well.
As of now, no significant link between alcohol and PD has been established. Further research is required to take a concrete stand in this regard.
Gut Bacteria May Play A Role In Parkinson’s
Considering how dependent we are on microbes (on and in our bodies) to function normally, why haven’t we paid enough attention to microbial causes of PD? Even more so because our poop can give us 350 times the information our genes can.18
Recent research suggests a link between gut bacteria and PD.19 In the study, mice were genetically manipulated to overexpress alpha-synuclein. Maintaining a control group of germ-free mice, the other mice were given gut bacteria either from healthy individuals or from those with PD. Gut bacteria seemed to accelerate PD progression and worsened symptoms. Gut bacteria may further instigate alpha-synuclein production in individuals who already have high levels of the protein and may also provoke brain inflammation, thus, causing PD.
The Best Way Forward
It is an emotional challenge to live with Parkinson’s or live with someone who has Parkinson’s. However, there are ways we can adapt our lifestyles to meet the shortcomings that are part and parcel of this mysterious condition. Being more open about our feelings with people we can trust and people who are in the same predicament as us can go a long way in fighting PD.
References [ + ]
|1.||↑||Parkinson’s Disease Information Page. National Institute of Neurological Disorders and Stroke.|
|2, 12, 13.||↑||Parkinson’s Disease. NIH Senior Health.|
|3.||↑||What is Parkinson’s Disease? Parkinson’s Diseases Foundation.|
|4.||↑||Parkinson’s Disease. National Institute of Environmental Health Sciences.|
|5, 7.||↑||Klein, Christine, and Ana Westenberger. “Genetics of Parkinson’s disease.” Cold Spring Harbor perspectives in medicine 2, no. 1 (2012): a008888.|
|6.||↑||What is Parkinson’s Disease? Parkinson’s Diseases Foundation.|
|8, 15.||↑||Acosta, Sandra A., Naoki Tajiri, Ike de la Pena, Marina Bastawrous, Paul R. Sanberg, Yuji Kaneko, and Cesar V. Borlongan. “Alpha‐Synuclein as a Pathological Link Between Chronic Traumatic Brain Injury and Parkinson’s Disease.” Journal of cellular physiology 230, no. 5 (2015): 1024-1032.|
|9.||↑||Reeve, Amy, Eve Simcox, and Doug Turnbull. “Ageing and Parkinson’s disease: why is advancing age the biggest risk factor?.” Ageing research reviews 14 (2014): 19-30.|
|10.||↑||Haaxma, Charlotte A., Bastiaan R. Bloem, George F. Borm, Wim JG Oyen, Klaus L. Leenders, Silvia Eshuis, Jan Booij, Dean E. Dluzen, and Martin WIM Horstink. “Gender differences in Parkinson’s disease.” Journal of Neurology, Neurosurgery & Psychiatry 78, no. 8 (2007): 819-824.|
|11.||↑||Nandipati, Sirisha, and Irene Litvan. “Environmental Exposures and Parkinson’s Disease.” International Journal of Environmental Research and Public Health 13, no. 9 (2016): 881.|
|14, 16.||↑||Jafari, Siavash, Mahyar Etminan, Farhad Aminzadeh, and Ali Samii. “Head injury and risk of Parkinson disease: A systematic review and meta‐analysis.” Movement Disorders 28, no. 9 (2013): 1222-1229.|
|17.||↑||Bettiol, Silvana S., Tanith C. Rose, Clarissa J. Hughes, and Lesley A. Smith. “Alcohol consumption and Parkinson’s disease risk: a review of recent findings.” Journal of Parkinson’s Disease 5, no. 3 (2015): 425-442.|
|18.||↑||Carlin, Martha. Do Gut Microbes Predict or Cause Diseases like Parkinson’s? TEDxBoulder|
|19.||↑||Could Parkinson’s disease start in the gut? Behind The Headlines – Health News from NHS Choices.|