Rachel Anders

Bio 151: Mechanisms of Neuron Death

Robert Sapolsky

Nov 6, 2018

The Environment and Parkinson’s Disease

Parkinson’s Disease is the second most prevalent neurodegenerative disease in the United

States, behind Alzheimer’s. The disease impedes dopaminergic signaling in the substantia nigra,

which eventually inhibits the motor cortex through a long cascade of neuronal signaling. About

10% of PD cases are familial while the rest are late-onset, occurring usually after 65 years and

progressing with age. While the specific cause of PD is still unknown, scientists have proposed

several environmental and genetic risk factors. In this paper, I will discuss the influence of

environmental toxins on Parkinson’s Disease. Though much time has been spent trying to find a

single cause, research suggests that the disease stems from a combination of both genetic and

environmental factors.

Pesticides

In July 1982, doctors in Santa Clara County, California, were surprised to see a large

number of patients present with severe symptoms of Parkinson’s Disease. They had the

characteristic rigidity and tremor of PD, but the symptoms had appeared overnight, and most

patients were under the age of 50. As investigators found out, these patients had all recently used

a new “synthetic heroin” containing a chemical called MPTP. This chemical acts by

accumulating in the mitochondria of a nerve cell, inhibiting ATP production. As the

mitochondria become more and more inefficient, O2 radicals are overproduced, which then
inactivate the neurotransmitter dopamine. This reduction in dopamine leads to degeneration of

neurons in the substantia nigra, which eventually leads to impairment of the motor system. This

California case is perhaps the most famous example of Parkinson’s Disease stemming from

strictly an environmental factor, and it has led to further studies of environmental toxins.

MPTP is very similar in structure to the commonly-used herbicide Paraquat. Further

research supports the link between MPTP and PD, showing that farmers who frequently use

pesticides have a much higher risk of developing PD. Additional evidence comes from

well-water drinkers. Private wells are usually built only 20 feet below the surface and are not

closely monitored for contaminants. Thus, different pesticides can leak into the water. As a

result, studies suggest there is up to a 90% increase in risk of developing PD among

well-drinkers (Langston). Alarmingly, Paraquat is still allowed in the US although it has been

banned from European countries since 2007. Despite the evidence pointing to MPTP as an

environmental risk, not all farmers exposed to pesticides develop PD, suggesting that there are

other factors at play.

Caffeine and smoking

Caffeine consumption and smoking are two other environmental factors that have been

linked to PD. One longitudinal study from Honolulu followed over 8000 Japanese-American

men over the course of 30 years, measuring the prevalence of PD. They found that those who

developed PD drank little or no coffee; in fact, men who drank 4 cups or more a day saw a 5-fold

reduction in risk of disease, compared to non-drinkers (Moss). This study has been replicated

several times and similar results have been found in women. Additionally, decaffeinated coffee

has been found to have no effect, pointing to caffeine -- and not some other component of coffee
-- as the protective agent. These protective benefits are unsurprising given the dopaminergic

effects of caffeine. Caffeine acts by blocking adenosine receptors in the brain, which normally

inhibit neural activity and cause sleepiness. Additionally, caffeine stimulates the production of

dopamine in the brain’s reward pathway, which is how caffeine can become addictive. Although

the reward pathway is separate from the dopaminergic pathway for motor function, scientists

believe caffeine stimulates overproduction of dopamine in the substantia nigra, as well. Thus, it

seems caffeine is correlated with a reduction in risk of developing PD because it increases the

amount of dopamine in the brain, delaying neuron degeneration.

In addition to caffeine, epidemiologic studies have consistently found that smokers have

lower rates of PD than non-smokers. The implications are counterintuitive: how could cigarette

smoking, which is linked to a number of adverse health outcomes, be protective? It also seems

the protective effects of smoking are dose-dependent: the more a person smokes, the less likely

he or she will develop PD. One study investigated pairs of identical twins in which one had PD

and one did not. For these twins, who shared the same genes and a similar environment, those

who smoked were less likely to develop PD than non-smokers.

Although the correlation between smoking and PD is clear, the exact mechanism is

unknown, and causation still cannot be determined. Perhaps it is PD that protects against

cigarette smoking, rather than the other way around. Because people with PD have lower levels

of dopamine, they may be less likely to become addicted to nicotine in the first place, making

them less likely to smoke. The most popular hypothesis is that nicotine is the chemical that

protects against PD. Nicotine mimics acetylcholine, which is known to act on dopaminergic

transmitters and increase levels of dopamine, thus creating a protective effect against PD.
However, randomized control trials have tried to use a nicotine patch as a medication for people

with PD, and results have been inconclusive. So, although smoking, like caffeine consumption, is

correlated with a reduced risk of PD, a causal relationship can’t yet be determined.

Genetic Risk Factors

Because PD has been observed across generations of certain families, scientists are

certain of some genetic component to the disease. Although only a small percentage of people

with PD share a family history of the disease, a large part of research has been spent trying to

find the elusive PD gene. Genetic risk factors generally fall into two categories. First are the

genes that cause familial PD, which account for <5% of cases. These are autosomal dominant

mutations, seen in a clear pattern across family generations and resulting in PD in almost all

cases. Second are susceptibility genes that are not causal but increase one’s risk of developing

PD. The susceptibility genes are common, occuring in up to 25% of the general population, but

have small effects. Scientists have identified several genes that can increase a person’s risk for

PD, and perhaps the most important is alpha-synuclein.

The alpha-synuclein gene encodes the alpha-synuclein protein, which accumulates in PD

brains in the form of Lewy bodies. Mutations in the alpha-synuclein gene can lead to

overproduction or abnormal formation of the protein, which then can lead to neuronal

degeneration. However, not all those with mutations in this gene develop PD. Similarly, not all

who are exposed to environmental toxins develop the disease. Most research suggests that it is a

combination of genetic and environmental factors acting on one another that increase a person’s

risk of developing PD.

 For example, consider the fact that men are 1.5 times more likely to develop PD than

women. Numerous environmental and genetic factors may be responsible, rather than just a

single cause. First, gendered roles in occupation present men with more risk, since men are more

likely to be farmers and be exposed to pesticides. Second, women may be protected by estrogen,

a powerful antioxidant which decreases the amount of O2 radicals in the body. Finally, genetics

may play a role: recent studies have localised a PD susceptibility gene called ​parkin​ to the X

chromosome, a finding that could potentially explain the higher incidence of PD among men.

Because men only have one copy of the X chromosome, the phenotype of a mutation can express

itself more easily than in women, who have two copies that can substitute for one another when

needed. Thus, it seems that a combination of environmental and genetic risk factors can account

for the prevalence of PD in any individual person.

Conclusion

Recent research points to several environmental toxins as risk factors of PD. Pesticide use

and well-water drinking are both correlated with an increase in PD, while caffeine consumption

and smoking are correlated with a decrease in risk. Similarly, certain genotypes carry an increase

in risk of developing the disease. However, no one factor acts alone as the causal agent of PD,

especially in non-familial cases. Rather, each individual case of PD is a combination of several

environmental and genetic factors acting on each other. Of course, research on these factors is

still ongoing, and results should be taken with a grain of salt. It isn’t sensible, for example, to

advise patients to begin smoking cigarettes in an attempt to reduce the risk of PD. Knowledge of

each of the factors related to PD can guide research and inspire new treatments for the disease.
Ultimately, PD is a result of both genetic and environmental risk factors, and understanding both

sides is paramount to understanding the disease.