Parkinson’s Disease: A Complex Trait Worth Understanding

Parkinson’s Disease, a disease many people are all too familiar with, is a serious neurological disorder that involves a long-term degeneration of the Central Nervous System (CNS). Parkinson’s, or PD for short, affects more than 10 million people globally and over 60,000 Americans alone are diagnosed with PD each year (GBD, 2016). People affected by this disease, a trait or combination of traits with environment, experience a variety of symptoms, typically including rigidity, muscular weakness, slow movement, tremors and problems with walking. The disease essentially affects every muscle tissue in the body, and also has serious neurological, cognitive, and behavioral consequences as well (Stoker, 2018). Parkinson’s is typically diagnosed in individuals over the age of sixty, mostly affecting the elderly population, but is also known to manifest at an earlier age in exceptional situations. Parkinson’s devastates the lives and families of countless people each year, and research to this day is intensive to not only understand the underlying causes and predispositions of the disease, but how it can be prevented effectively, diagnosed early, and treated. This paper will dive into several topics, including the history of Parkinson’s Disease from a historical and evolutionary perspective, how the disorder affects human reproductive fitness, the genetic/environmental factors that affect the trait’s evolution and inheritance, how the active trend toward complexity in evolution affected the rise of this disorder, as well as potential future studies that can be conducted to understand the transgenerational inheritance of the disease and it’s neuropathological mechanisms.

The first time Parkinson’s Disease was described qualitatively was in the 18th century by writers, who in their works described the observable aspects of the mysterious and unknown disorder. The most notable pioneer in describing Parkinson’s was James Parkinson, a surgeon for which the disease was named after. James Parkinson was the first person to study multiple individuals all showing symptoms of what is now referred to as PD (DJ, 2010). In 1817, he published the first objective analysis of the disease, called An Essay on the Shaking Palsy. At the time, he coined the disease shaking palsy, more formally paralysis agitans. The essay goes on to note the progression of the disease over time, the types of tremors and involuntary movements observed, and roughly the cognitive effects associated with the disease (Parkinson, 1817). The modern name coined for the disease came decades later from a neurologist and scientist named Jean-Martin Charcot. Charcot was one of the most important individuals in the history of Parkinson’s Disease research, since he was the first scientist to distinguish between weakness, tremors, rigidity, and slowness of movement initiation (bradykinesia). He also was the first to describe variation within the disease itself, specifically differences between classical PD and PD with hyperextension characteristics. Charcot went on to rename the disease after James Parkinson, giving the modern term for the disease, Parkinson’s Disease (Kumar, Aslinia, 2011). Other important historical advances in the study of Parkinson’s disease included the work of Frederic Lewy in 1912, for whom Lewy bodies are namesake, and also the work of Konstantin Tretiakoff, who described the region of the brain affected, being primarily the substantia nigra (Silva et al., 2010) . More modernly, another important advance in PD research was the development of an effective treatment, Levodopa, L-DOPA for short, which is a dopamine promoter developed by Casimir Funk in the early 1900s, but remained overlooked as a potential treatment until the mid-20th century. When L-DOPA entered common use in 1967, it was revolutionary and brought upon a new horizon of research for managing not only Parkinson’s disease, but many other neurodegenerative conditions as well (Sveinbjornsdottir, 2016). Other treatments have arisen since then, ranging from neural stimulation to neuroactive medications. The slow and deadly nature of Parkinson’s disease results from two main mechanisms, one being the cellular death of the brain’s basal ganglia, and the other being from the accumulation of the protein alpha-synuclein in the neurons, also referred to as Lewy bodies. These two mechanisms affect the brain, and all tissues in the CNS as a whole, eventually resulting in complete lack of neuromuscular control, and eventually respiratory failure. Typically, before respiratory failure takes place, the patient will die from respiratory infection or falls. The average life expectancy of a PD patient from the day of diagnosis is 7-15 years (Stoker, 2018). To this day there is no cure for Parkinson’s Disease, but many are hopeful that current and future research will eventually yield a final cure for this devastating complex trait.

The cause of Parkinson’s Disease has not yet been completely described, and research indicates that it is likely a combination of environmental and genetic factors that give rise to the trait. The multifactorial nature of PD is what makes it a complex trait. Environmental factors such traumatic CNS injury (chronic or acute), and exposure to certain biocidal agents have been positively correlated with prevalence of Parkinson’s with current research but the relationship not completely defined yet. Other environmental factors such as exposure to certain metals and certain solvents such as Trichloroethylene have shown positive correlations with higher incidence of Parkinson’s as well, but these factors are difficult to study due to it being a nearly exclusive disease to humans, which makes effective research and broad statistic in a reasonable period of time rather difficult (parkinson.org, 2020). Surprisingly, for once cigarettes might not be such a negative drug. Multiple peer reviewed studies have shown that tobacco use reduces the risk of developing Parkinson’s. Other substances that decrease risk of developing PD include use of NSAIDs, use of Statin-class medications, high vitamin D levels, exercise, high levels of blood urate, and caffeine. It is a surprising reality that some substances typically perceived to be only harmful can have some health benefits, especially with at-risk patients. Environmental factors affect many outcomes in the health of an individual, and changes the probabilities of development, whether higher or lower, in nearly all multifactorial genetic diseases. The other component of causation of Parkinson’s Disease is the genetic factor, likely more determining than the environmental factors itself, as many individuals with no genetic abnormalities don’t consume or become exposed to the substances listed above and still don’t develop PD. From current studies, between 10-15% of all Parkinson’s Disease cases are solely genetically linked. Currently, there are dozens of genetic mutations positively correlated with Parkinson’s, some much more than others. The genetic mutations studied have included both autosomal dominant inheritance patterns and autosomal recessive inheritance patterns, which can make it tricky to develop a proper pedigree to evaluate risk or treatment. One study shows that 5% of the people with classical Parkinson’s have an associated mutation in the GBA1 gene (Stoker, 2018). With so many genes showing positive correlation to rate of incidence, studies have shown that having multiple PD mutations can increase the risk 30 times or more than without the mutations. Patients with multiple genetic mutations in those genes, and environmental exposure, show earlier onset of PD at a much younger age, in some cases with individuals in their thirties and forties (Stoker, 2018). The inheritance of those mutations, inheritance of environmental imprints, and role of epigenetics and embryonic environmental conditions will be discussed later in the paper.

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The evolutionary history of Parkinson’s Disease is one that is unique, multifactorial, and relatively difficult to study. Firstly, Parkinson’s is one of the two major neurodegenerative disorders that are specific to Homo sapiens, the other being Alzheimer’s Disease. The scientifically probable reason that it is unique to humans, unlike other neurological disorders such as muscular dystrophy and narcolepsy, has several perspectives (Diederich, Surmeier, et al, 2019). The first perspective, also the major cause of the most observable characteristics of the trait, is the unique anatomy of the human brain compared to closely related mammals and other vertebrates over evolutionary time. Over time, our neurological wiring, in a casual sense, has reworked itself to allow the intelligence and cognitive ability we have today. As a side effect though, these anatomical and physiological changes can allow buildup of the Lewy bodies, or clumps of protein, to form in predisposed individuals. This has been artificially replicated in non-human primates but has never been naturally observed. Other primates can experience neural degeneration over time, as a result of aging in captivity, but the degeneration is not affected by L-DOPA intervention nor accompanied by the Lewy bodies, so it would not classify as Parkinson’s Disease or as Alzheimer’s Disease (CC, 2015). Our brains have anatomically grown in scale as well, almost tripling some of our cousins, and with such a complex and sensitive organ like the brain, there is likely to be deleterious effects as well as the beneficial effects, like myself being able to write this paper (CC, 2015). If this growth was to be attributed to higher gene expression, less control essentially, higher energy requirement would be attributed to the growth. One study suggests that this cerebral growth over evolutionary time was one of the driving factors of the omnivore diet that Homo sapiens adapted, to meet the energy requirements without major adaptation of our digestive tracts to accommodate the huge amount of plants needed to match the calorie and protein consistency of animal flesh (Diederich, Surmeier, et al, 2019). This hypothesis was appropriately coined “The Expensive-Tissue Hypothesis”(Aiello & Wheeler, 1995). Another interesting effect of the evolution of our brains pertaining to Parkinson’s Disease was the ultra-utilization of the SNc dopaminergic neuron pathways. According to one study, the number of dopaminergic neurons per a given striatal volume in humans is only a tenth of the number observed in the average rodent (Diederich, Surmeier, et al, 2019). On the other hand, that means the dopaminergic neurons innervate much, much more per neuron than that of the common rodent. The consequence of such a dramatic increase in workload, on something as sensitive as a neuron’s axon terminal, could be the evolutionary key to why Parkinson’s Disease occurs only in humans, as those dopaminergic neurons start to degrade very quickly once the onset of PD begins. Going back to the increase in energy demands, this need for energy could help researchers understand why the degeneration begins (Diederich, Surmeier, et al, 2019). To meet these demands, that brings back to the table the biologists’ favorite organelle, “the powerhouse of the cell”, the mitochondria. As discussed in the third section of this paper, relevant mutations can increase the likelihood of developing Parkinson’s. If there were mutations present in an individual that affect the neuron’s mitochondrial structure, functions, and efficiency, which could lead to deficit of energy, the neuron’s most sensitive component, the axon terminal, could begin to become damaged and show evidence of neurodegeneration. That would be highly characteristic of early stage Parkinson’s and could predispose individuals to the trait if they had the appropriate mutations to affect the mitochondria deleteriously. On a non-genetic note, mitochondrial function is also subject to environmental conditions as well. If there was a toxic substance, obtained from the environment or even from an infection byproduct, that affected mitochondrial function, that could produce similar results to the mutation-level effects on the mitochondria. Another factor too is that mitochondrial efficiency and function decreases with age, which would explain why individuals over the age of 60 are most likely to develop Parkinson’s Disease. These theories drive home why Parkinson’s is a highly complex trait. It involves the most important, complicated, and sensitive organ in the modern human, our brain, and can vector from varying ratios of genetic, environmental, and age-related factors.

The inheritance of genes that can predispose you to Parkinson’s Disease is another interesting part of this complex trait. As stated before, there are many studied mutations on certain genes that can predispose an individual to Parkinson’s Disease. These of course, can be passed onto offspring if the mutation affects germ cells and not just somatic cells. Whether it be a mutation affecting mitochondrial function, or a mutation affecting stability of axon terminals or a component, they can all be passed down to offspring. The different mutations are inherited in various ways, with some being autosomal dominant, some being autosomal recessive, and mitochondrial mutations being only passed from the maternal parent to the offspring. That does pose the question, “Well, why didn’t natural selection select against those mutated genes?”. The answer is that Parkinson’s doesn’t affect humans, at least historically, that are actively breeding and producing offspring. The disease only manifests in old age, so in almost all cases, especially with females, they would have already had children and passed those genes on before the disease affected them (Garcia-Ruiz & Espay, 2017). With that being the case, Parkinson’s Disease does not directly lower reproductive fitness, as affected individuals typically have no symptoms at the age of which breeding would occur. Another interesting fact is that Parkinson’s is way more prevalent now than it was before. “Why?” you might ask, but the answer is not completely known. The best hypothesis for why it’s more prevalent is that the average life expectancy of a human is higher now, than it has ever been. Before antibiotics, modern medicine, food security, etc, humans would typically die at a much younger age, before serious symptoms would present. This hypothesis would explain as well why the trait was preserved through evolutionary time, humans typically didn’t make it that long. It also explains why it wasn’t reported more in historical records, or at least the symptoms (Garcia-Ruiz & Espay, 2017). It’s already rare to have this condition in general, let alone when the average life expectancy was 45-55 years old and the symptoms wouldn’t seriously present until around age 60 in most cases. Since the most probable rise of PD was a consequence from evolutionary changes to our brain’s anatomy and physiology, it likely never lowered reproductive fitness on a population level as selection would drive our neurological development forward to make better tools, and have better cognition which would massively increase reproductive fitness. The “fine-tuning” for this complex trait, at least in a sense, would be that combination of environmental factors with the genetic predisposition. If you are already predisposed genetically to Parkinson’s Disease, there is still a low chance of displaying the affected trait, but if combined with some environmental toxin that increases the likelihood of Parkinson’s, that in a way would fine-tune the trait. I think evolution of the human brain is also a part of the fine-tuning, in that as the size of the axon terminal increased, along with energy requirements, the mutations that affected mitochondrial or axon function would be more deleterious, as more reliance and efficiency was needed to accommodate those adaptive neurological changes. The inheritance of genotypes that predispose an individual to Parkinson’s Disease is already established, but there is still much more to learn about how the environment affects the end trait, if epigenetic imprinting plays a role, as well as identifying new mutant or wild-type genes that positively correlate with an increased risk of PD. It’s hard to conduct research on an affected trait that’s only present in humans, as that greatly reduces the ability of scientists to control conditions enough to isolate environmental causes, and study the inheritance of those genes through many generations. There is still much work to be done to help cure Parkinson’s Disease.

If I could propose one study that would allow for a greater understanding of the evolution, inheritance, and fine-tuning of Parkinson’s Disease, I would focus on understanding the role of human development and environmental conditions on the likelihood of the disease manifesting. For investigating the environmental conditions, the study would concern living brain tissue, extracted from a deceased donor, specifically from a young, healthy individual who hasn’t presented with the disease, but has multiple genetic predispositions for the disease. Scientists could subject the cell lines of dopaminergic neurons to different environmental conditions, such as low vitamin D versus sufficient vitamin D, no nicotine/caffeine versus nicotine/caffeine, etc, and analyze the amount of neuron degeneration or cell death over time (Parkinson.org, 2020). Another way to do this study would be with monozygotic twins, where the twins are both nearly genetically identical, have genetic predisposition to Parkinson’s, but one twin smokes and drinks coffee every day, while the other doesn’t. After they reach the threshold age for symptoms to present, analyze CAT/CT scans of the brain to look for differences in neurological function or cell death, and also have them perform a series of reflex tasks to analyze reflex times. Twin studies can be useful as well for analyzing the effects of development if the twins were separated at birth. If after 60 years of different environmental factors, you could analyze similar to the last proposal and look for signs of varying neurological function between the two.

I think Parkinson’s can serve as a great example of why Evolution always favors complexity, and always to higher levels of complexity. The evolution of the trait itself is indicative of just how complex our brains really are, and how much they have changed over evolutionary time. If you look at our DNA, it's gotten progressively longer over the evolutionary clock when compared to insects, and then to multicellular microorganisms, and then to single cell eukaryotes, and then to prokaryotes, along with the number of proteins produced, and the overall complexity of the final organism. It’s worth noting that for an increase in complexity to take place, there must be a selection for complexity. We still have prokaryotes on Earth, not much different than they were billions of years ago. In a basic sense, things that already work perfectly are going to be under minimal selection, such as thermophilic prokaryotes. With human evolution, and Parkinson’s, we have constantly gotten more complex, so complex at this point that the best scientists in the world can’t fully understand yet what the true cause is of Parkinson’s as a whole picture, and the relationships between the thousands of variables involved. As a closing statement, if selection is present and strong enough, evolution will tend to move towards complexity, if selection is minimal, then the rate at which complexity arises will be minimal (Yaeger, 2009).