A Neurodegenerative Disease
Parkinson’s disease (PD) is a neurodegenerative disease that creates a chronic and progressive disorder of the nervous system. Medical understanding of the development and progression of PD pathology is not yet complete. However, it is known that a complex interplay of multiple environmental and genetic factors are involved in the pathogenesis of PD. It is likely that PD is a syndrome rather than a single disorder. In other words, PD has a collection of signs and symptoms that characterize the disease.
For most Parkinson’s sufferers, symptoms take years to develop and slowly progress over time. The disease involves the malfunction and death of vital nerve cells in the brain, called neurons. (A neuron is a cell that carries electrical impulses.) Parkinson’s ultimately claims dopamine-releasing neurons in a small, central arc of the brain called the “substantia nigra pars compacta.” When nigral neurons die, motor function goes awry and the classic symptoms set in. The first symptom is often a barely noticeable tremor in just one hand. However, gastrointestinal problems often precede motor symptoms by many years. Signs of PD include resting tremors of the hands, limbs, and face, slow movement, rigidity of the limbs and trunk, slurred speech, and impaired balance. Nonmotor functions such as sense of smell and sleep regulation can also be affected. Parkinson’s disease can be profoundly frustrating, as walking, talking, and even eating become more difficult and time-consuming.
Alpha-synuclein: The hallmark of Parkinson’s Disease
Alpha-synuclein is a protein that is abundant in the human brain. It is extensively localized in brain neurons and at the synapses, the connections established between neighboring neurons where the exchange of electrical signals and neuronal communication takes place. At normal levels, alpha-synuclein accelerates the release of neurotransmitters — the vesicles containing molecules to be delivered to other neurons to activate them. However, increased expression of this protein inhibits the mechanism through which neurons release neurotransmitters and the accumulation of alpha-synuclein becomes toxic to the neurons. Scientists hypothesize that this could lead to the impairment of dopamine release, and ultimately to cell death. Several genetic mutations encoding for alpha-synuclein leads to Parkinson’s. However, scientists believe that non-genetic defects in alpha-synuclein’s mechanism of action are also at the root of Parkinson’s disease.
Decline in Dopamine Producing Neurons
The onset of molecular and cellular neuropathology of Parkinson’s likely occurs decades before the earliest symptoms appear. Symptoms are related to the slow decline of dopamine, a neurotransmitter. By the time symptoms appear, damage likely has progressed over an estimated 5 to 15 year period with an estimated loss of 60%-80% of the dopamine-producing neurons.
Current therapies treat these symptoms by replacing or boosting existing dopamine; however, these therapies have limited therapeutic benefit in the long run. Research indicates that L-dopa therapy of PD patients may induce oxidative stress, increase the levels of inflammation, and lead to cell death — apoptosis. Also, only parts of the brain need more dopamine but other parts do not. So when the parts of the brain that regulate emotional states and motivation have elevated domine levels, the patient may experience heightened emotional states and compulsive behaviors.
A Rare Disease
Although Parkinson’s is one of the most common neurological diseases in elderly people, thankfully, it is rare. About one million Americans, out of about 330 million, have it. In 2000, a meta-analysis confirmed an association between pesticide exposure and increased risk of Parkinson’s. This could explain the reason why farmers are more prone to Parkinson’s disease than the general population. A nine-year study found that patients exposed to pesticides had a 70% higher incidence of Parkinson’s at the study’s conclusion in 2006.
The scientific literature suggests an association between impaired detoxification and many diseases, including Parkinson’s. Studies have found that one’s ability to efficiently detoxify and remove xenobiotics can affect the progression of Parkinson’s, as well as other chronic disease processes. (Xenobiotics are chemicals that are not expected to be present within an organism.) N-acetyltransferase plays important roles in the metabolism and detoxification of xenobiotics and therapeutic drugs. Associations have been found between slow metabolism through the N-acetyltransferase pathway and high risk of Parkinson’s disease and some cancers. It has also been found that those having a genetic variation in a subtype of the ALDH enzyme, an enzyme that helps metabolize fats, proteins, and toxins, increased the risk further in those exposed. It is believed that most cases of PD are due to gene-environment interactions.
An Infectious Protein
Some forms of Parkinson’s disease are associated with an overproduction of a protein called “alpha-synuclein.” Alpha-synuclein occurs naturally in the nervous system and is abundant in the brain. However, in some neurodegenerative diseases, these proteins fold abnormally, clump together, and accumulate in neurons. This misfolded protein can spread through the nervous system as a prion, or infectious protein. In 2005, researchers found that people with Parkinson’s disease who had an accumulation of this protein in the neurons in their brains also had it in the neurons in their gastrointestinal tract.
Two Main Nervous Systems
We have two main nervous systems: central and autonomic. The central nervous system (CNS) is made up of the brain, spinal cord, and peripheral nerves such as sensory and motor nerves. The autonomic nervous system (ANS) regulates vital functions such as breathing, heartbeat, and digestion. The ANS is comprised of the sympathetic, parasympathetic, and enteric nervous systems.
The Enteric Nervous System: Our Other Brain
The enteric nervous system consists of a mesh-like system of neurons that governs the function of our gastrointestinal tract. This network of neurons extends from the esophagus to the anus. It contains an estimated 200-600 million neurons — roughly the number in a cat or dog’s brain. The enteric nervous system is so extensive it has been dubbed “our second brain.” It can function as an independent entity without input from our central nervous system, although they are in regular communication. Our brain and gut are connected by a network of neurons called the vagus nerve. The vagus nerve connects the brain stem to the abdomen and serves as a branch of the information highway between the two nervous systems.
Parkinson’s May Start in the Gut
In most studies on Parkinson’s disease, the brain has been the focus of the research. However, in 2015, researchers demonstrated how proteins altered in the gut lumen could move from the gastrointestinal tract into nerve cells. This alteration or corruption of proteins is thought to be due to interactions with pesticides or an infection. Further research has led to the hypothesis that the prions causing Parkinson’s disease could spread from neurons in the gut lining to the neurons in the brain via the vagus nerve. Research also suggests that these prions can travel from the brain to the gut, again through the vagus nerve.
The Gut Microbiota: Involved in the Pathogenesis
In 2017, researchers found yet another reason to believe the gut plays an integral role in the development of Parkinson’s disease. There is considerable evidence that the gut microbiota are involved in the pathogenesis of Parkinson’s disease, as well as other neurodegenerative diseases. Studies suggest that PD alters the composition of the intestinal flora, which in turn accelerates pathology.
Our gut microbiota play important roles in both our immune and nervous systems’ function. Microorganisms in our digestive system have been found to play an important role in breaking down xenobiotics. A recent study showed major disruption of the normal microbiota in individuals with Parkinson’s. Also, when certain gut bacteria break down dietary fiber, they produce molecules called short-chain fatty acids (SCFAs), such as acetate and butyrate. Research has shown that these molecules also can activate immune responses in the brain. It is hypothesized that an imbalance in the levels of SCFAs regulates brain inflammation and other symptoms of PD.
Parkinson’s Patients Relative to Control Group
Researchers have found increases in the Firmicutes family, in unclassified bacteria, and in the genus Akkermansia, but found decreases in Prevotella and Eubacterium genera in PD patients relative to controls. At the species level, men with PD had an overabundance of Akkermansia muciniphila and Alistipes shahii, but fewer Prevotella copri, Eubacterium biforme, and Clostridium saccharolyticum. Both Prevotella and Eubacteria produce short-chain fatty acids (SCFAs). It is hypothesized that SCFAs have an anti-inflammatory effect in the human gut, and perhaps a therapeutic effect in the brain — potentially a mechanism by which neuroinflammation (which is a component of the Parkinson process in the brain) is influenced by the microbiota.
Importance of Early Diagnostics
Early diagnostics are important for Parkinson’s disease prevention and intervention. Identifying at-risk individuals before the onset of disease provides us with the ability to implement interventions that may slow or stop the course of the disease. Traditional biomarkers providing early diagnosis of the disease include those of imaging, cerebrospinal fluid, oxidative stress, neuroprotection, and inflammation. Currently, genomic analysis holds the most promise.
Precision Medicine — Key to Parkinson’s Disease Prevention
Precision medicine has the ability to predict, on an individual basis, factors contributing to the susceptibility to the development of Parkinson’s disease, and is, therefore, key to early diagnosis. Recent advances in our understanding of genetic factors underlying PD offer the potential for identification of at-risk individuals and possibly preventing the onset of disease through treatment. And, if further research supports the prion and altered microbiome hypotheses, this could point the way to new ways to diagnose Parkinson’s disease early on, as well as new approaches to its prevention and treatment.
At The Harlin Center for Precision Medicine, we look at a panel of genes associated with Parkinson’s disease. In particular, we look for LRRK2 and GBA, each of which increases risk. The LRRK2 increases risk by 25 percent and GBA increases it four-to-five fold. But if a person of Ashkenazi Jewish background inherits LRRK2, the risk increases eightfold. We also look at biomarkers associated with inflammation and oxidative stress.
Polymorphisms in Cyp2D6 gene, associated with metabolism, are associated with a high risk of early-onset Parkinson’s disease in Caucasians, especially in white British subjects.
Parkinson’s Disease Prevention
Minimizing xenobiotic exposure has been shown to slow the progression of Parkinson’s. And some research has shown that regular aerobic exercise may reduce the risk of developing the disease. For those with early symptoms, an exercise program designed by a physical therapist may be advised. Adoption of a healthy lifestyle and a healthy anti-inflammatory and anti-oxidant rich diet, before symptoms appear, is key to Parkinson’s disease prevention.
- Sulzer D, Zecca L. Intraneuronal dopamine-quinone synthesis: a review. Neurotox. Res. 2000;1(3):181–195. [PubMed]
- Khan FH, Saha M, Chakrabarti S. Dopamine induced protein damage in mitochondrial-synaptosomal fraction of rat brain. Brain Res. 2001;895(1-2):245–249. [PubMed]
- Andican G, Konukoglu D, Bozluolcay M, Bayülkem K, Firtiina S, Burcak G. Plasma oxidative and inflammatory markers in patients with idiopathic Parkinson’s disease. Acta Neurol. Belg. 2012;112(2):155–159. [PubMed]
- Dorszewska J, Kozubski W. Oxidative DNA damage and the level of biothiols, and L-dopa therapy in Parkinson’s Disease. In: Rana A.Q., editor. Etiology and Pathophysiology of Parkinson’s Diease In Tech. 2011. pp. 349–372.
- Berman SB, Hastings TG. Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J. Neurochem. 1999;73(3):1127–1137. [PubMed]