The Genetics, Pathophysiology, and Developing Therapies Concerning Parkinson's Disease

Abstract

Parkinson’s disease is one of the most common neurodegenerative disorders in the world. It is a movement disorder caused by the deterioration of dopamine producing cells in a portion of the midbrain called the substantia nigra. Understanding the etiological mechanisms that contribute to this disease, as well as the pathophysiology of the disease and its related symptoms has contributed to advances in treatments and diagnostic procedures. The definitive causes of the disease are still in the works of being determined; however, an abundance of research has opened doors to identify potential origins. The purpose of this literature review is to explore the pathophysiology, etiology, treatments, and research directed toward Parkinson’s disease.

Introduction

Parkinson’s disease (PD) was first characterized in 1817 by James Parkinson, an English physician that conducted extensive research into the disease that he described as the “shaking palsy” (A History of Parkinson’s, 2019). However, it was not until the 1870s that the disease was actually named Parkinson’s disease. French neurologist Jean-Martin Charcot named the disease after Parkinson in order to honor his studies and compilation of the multiple symptoms related to the disease. (A History of Parkinson’s, 2019). James Parkinson was ultimately responsible for distinguishing PD from other diseases exhibiting similar symptoms, such as multiple sclerosis and other neurodegenerative disorders (Goetz, 2011).

Parkinson’s disease is characterized by four defining cardinal sings: resting tremor, bradykinesia, rigidity, and postural instability. The chronic and progressive nature of PD causes these symptoms to worsen over time. Symptoms may be hardly noticeable at the onset of the disease; however, progressive PD may lead to severe motor impairment (Mayo Foundation, 2019). Currently, Parkinson’s disease is considered an idiopathic disease, meaning the cause is unknown. As with many other neurodegenerative diseases, this disease primarily arises with age. Most people with Parkinson’s first develop the disease at median age of 60; however, there are rare scenarios in which PD can begin before or around the age of 50. In this case, Parkinson’s may be linked to gene mutations. In addition, statistically Parkinson’s disease affects about 50 percent more men than women (National Institute, 2019).

Pathophysiology

The development of Parkinson’s disease is most directly related to the decline in function, degradation, and cell death of the neurons that produce the hormone dopamine—termed dopaminergic neurons (Eriksen et al., 2005). These neurons are located in the substantia nigra pars compacta, which is the nucleus in the midbrain component of the brain (Know Your Brain, 2014). The overall mechanism behind neurodegeneration is still unknown, however, this process is ultimately what leads to the loss of motor function in PD patients as well as some impaired behaviors including learning and emotion (Eriksen et al., 2005).

The loss of function of the dopaminergic neurons leads to the decreased affinity for dopamine, which leads to further changes in the basal ganglia pathways, including alterations of other neurotransmitters such as glutamate, GABA, and serotonin (What is Parkinson’s, 2019). In regions of the brain with decreased dopaminergic function, Lewy bodies are present. Lewy bodies are abnormal aggregates made of insoluble fibers containing misfolded proteins. These irregular aggregates are, in general, protein inclusions that form in the neurons of people with Parkinson’s disease (What Is Parkinson’s, 2019). Within these Lewy bodies, a protein known as alpha-synuclein contains toxic protofibrils that are proven to mediate disruption of cellular homeostasis and neuronal death. Alpha-synuclein has also been identified to induce an inflammatory response within glial cells, which causes further neurodegeneration (Stefanis, 2012).

Etiology

Despite extensive research into the neuropathology of Parkinson’s disease, the mechanism in which PD is developed within an individual is yet to be completely understood. A combination of environmental and genetic factors has been investigated as causative agents of the disease; however, no definitive evidence supports a specific factor or trend for the etiology of PD. Despite this uncertainty, age contributes to the biggest risk factor for the development of PD, with the median age of development hovering around 60 years of age (Kouli et al., 2018).

As the second most common age-related neurodegenerative disorder, there have been investigations into what specific age-related factors predispose individuals to develop Parkinson’s disease (Reeve et al., 2014). Advancing age has proved to indicate affects in clinical progression of PD due to a faster rate of motor growth, reduced tolerance to the medications, more severe gait and postural disability, and increased cognitive impairment leading to dementia development in PD patients (Levy, 2019). In general, ageing affects many cellular processes that predispose neurodegeneration, and age-related changes in cellular function predispose to the pathogenesis of PD. The combination of age-related factors with the neurodegenerative effects of PD most likely lead to the acceleration of the disease. As individuals get older, the accumulation of unrepaired cellular damage as well as the weakening of cellular repair and compensatory mechanisms contributes to the impaired function of all cells, including brain cells. The effects of aging can even cause genetic effects in cells (Hindle, 2010). Age-related changes have been proven to contribute to the degeneration of the neurons of the substantia niga as well as a reduction in the striatal tyrosine hydroxylase and dopamine. A reduction of neurons in the substantia nigra may be the result of an accumulation of deletions of mitochondrial DNA. A reduction in the enzyme tyrosine hydroxylase and the neurotransmitter dopamine could result in the hypertrophy of neurons (Reeve, 20144). Though age-related causes are the primary independent risk factors for the development of PD, other potential risk factors for the development of PD may include tobacco usage and the lack of caffeine consumption (Kouli et al., 2018).

Ironically, cigarette smoking and tobacco usage has suggested to decrease the risk of PD development. Despite the many negative effects on the body associated with smoking, the presence of nicotine in the body has shown to activate nicotinic acetylcholine receptors on dopaminergic neurons. This activation of nicotinic acetylcholine receptors has shown to have neuroprotective effects in experimental modes of Parkinson’s disease (Kouli et al., 2019). Studies have suggested that the stimulatory effects of nicotine influence dopamine signaling and can ultimately protect against damage of dopamine-secreting neurons in the brain (The Connection Between Smoking, 2019).

Studies have examined decreased caffeine usage as a risk factor for the development of PD. Caffeine is an adenosine A2A receptor antagonist, which is believed to be protective in PD. Studies have been conducted in order to compare the development of PD with coffee-drinkers versus non coffee drinkers (Kouli et al., 2018). According to a study conducted in 2001, the analysis of the neuroprotective ability of caffeine was evaluated in a mouse model of PD, and the results confirmed that caffeine does exhibit an ability to prevent the degradations of the neurons that contribute to PD development (Chen et al., 2001). Another study identified that caffeine drinkers have a 25% risk reduction in the development of PD compared to non-caffeine drinkers (Noyce et al, 2012).  In addition, research has demonstrated that caffeine enhances dopamine signaling in the central nervous system. This is important because the dopamine-producing cells within the nervous system have been proven to contribute to the progression of PD (Coffee and Parkinson’s, 2019). 

Diagnosis:

As an idiopathic disease, there is no concrete evidence for the determination of Parkinson’s disease. One test that can be performed to narrow the patients’ symptoms down to a neurodegenerative disorder is to evaluate one’s response to dopaminergic medications. However, the dopaminergic responses could be representative of a different neurodegenerative disorder as well, such as Multiple System Atrophy (MSA) or Progressive Supranuclear Palsy (PSP).

The most definitive way to diagnose a patient with PD is the identification of the four most common clinical signs associated with the disease: slow movements (bradykinesia), decline of body movement (hypokinesia), rigidity, and resting tremor. The presence of all clinical signs is usually prevalent during later progressive stages of the disease, and it is up to the medical examiner to determine if a PD diagnosis is appropriate for the patient considering his or her symptoms. The UK PDS Brain Bank Criteria is a chart that identifies the excluding and supporting criteria for the diagnosis of PD. (National Collaborating Centre, 2006) Furthermore, aside from the obvious physical symptoms, the only way to official confirm Parkinson’s disease as a diagnosis is testing for the presence of Lewy bodies within brain tissues of patients post-mortem (National Collaborating Centre, 2006).

Treatments

Parkinson’s disease cannot be cured; however, there are several medications and even some surgical procedures that may help make patients more comfortable by alleviating some of the symptoms associated with the disease. In some cases, clinicians may even suggest a change in diet and exercise, or advise physical therapy to assist with mobility challenges (Mayo Foundation, 2019).

In terms of medications, there are a variety of anticholinergics, amatadine, adopamine agonists, COMT and MAO B inhibitors, and Carbidopa-levodopa. Anticholinergics mainly help to manage tremors associated with Parkinson’s Disease. Common anticholinergic medications include benztropine and trihexyphenidyl. In addition, amantadine is prescribed for patients that exhibit early stages of Parkinson’s disease, in which the symptoms are not as severe. Amantadine provides short-term relief of symptoms. Dopamine agonists work to mimic dopamine effects in the brain. These medications include pramipexole, ropinirole, and rotigotine. COMT and MAO B inhibitors prevent the breakdown of brain dopamine by inhibiting different enzymes. An example of a COMT inhibitor is Talcapone. Some MAO B inhibitors include selegiline, rasagiline, and safinamine. Lastly, Carbidopa-levodopa is the most effective medication for the treatment of Parkinson’s disease. Carbidopa-levodopa is a chemical that is converted to dopamine when transmitted to the brain. It ultimately influences the production of more dopamine in order to somewhat reverse the effects of PD in patients. Although Carbidopa-levodopa have proven to be very effective in the treatment of PD, a resistance to this medication can come with progressive stages of the disease (Mayo Foundation, 2019).

Surgical treatments have also been used to treat patients with Parkinson’s disease. One of the most common surgical techniques used in PD patients is Deep Brain Stimulation therapy (DBS). Deep Brain Stimulation is a surgical technique involving the use of a device to stimulate particular regions of the brain with electrical impulses by a battery operated neurostimulator. These electrical impulses are aimed to disrupt the abnormal signaling patterns in the brain that result in motor issues associated with Parkinson’s. (Surgical Treatments, 2019). This surgical method is used in an effort to improve several motor functions associated with PD progression: tremor, rigidity, stiffness, slowed movement and walking difficulties. This surgical treatment has been proven to improve these motor functions as well as reduce the requirement for dopaminergic medications. According to an article published in 2019 analyzing the benefits of DBS in PD patients, patients receiving the surgical therapy exhibited a 38% improvement in daily motor activity 4 years after receiving the treatment (Malek, 2019). Though there is a lot of room for improvement in motor activities of PD patients with DBS therapy, it is very costly, and usually reserved for patients that have previously exhausted all forms of medications (Surgical Treatments, 2019).

Future Direction

Due to the idiopathic nature of Parkinson’s disease, there have been very little efforts toward research in curing the disease as a whole. The uncertainty behind the mechanism of neuron degeneration make it extremely difficult to work toward a cure for a disease in which the mechanism of development is not fully understood. With this being said, much research is directed toward new treatment therapies that target specific symptoms of the disease and perhaps slow the progression of the disease. In recent years, studies have posed a particular interest in the use of virtual reality training in upper-limb motor regeneration therapy in PD patients.

Virtual Reality (VR) therapy has been investigated as a form of neurorehabilitation in PD patients. VR therapy programs are a computer-based technology that allow users to interact with simulated environments and receive feedback on performance within real-time scenarios, repetitive activities, facilitating motor learning and neuroplasticity through increased intensity during task-oriented training. A research study conducted in 2019 focused on the use of Leap Motion Control System (LMC) to evaluate effects of gaming-system usage within Parkinson’s Patients. LMC is a low-cost device that uses a sensor to capture upper body movements of the patients. Overall, the study suggested an improvement in upper limb coordination, speed of movement, and fine dexterity in PD patients over time. (Fernandez-Gonzalez et. al., 2019).

Another developing treatment for Parkinson’s Disease is the use of induced pluripotent stem cells, or iPSCs. Induced pluripotent stem cells are a type of stem cell that have been genetically reprogrammed in a lab to assume an embryonic stem cell-like state. With this, the interest in iPSC treatment for Parkinson’s disease resolves around the possibility of influencing these iPSCs to differentiate into neurons and other cells within the nervous systems that could potentially function as dopaminergic neurons (Emerging Research, 2019). A study published in 2019 analyzed patient-derived iPSCs for use in disease models of Parkinson’s disease and other neurodegenerative disorders. This study concluded that human iPSCs can be used as a reliable basis for the generation of neuronal cell types in order to explore the mechanisms underlying neurodegenerative diseases. The article suggests that further research into iPSC-derived neurons could lead to clinical evaluations in combination with gene editing systems and organoid engineering for the development of new therapies and, eventually, a possible cure for neurodegenerative disorders (Wu et al., 2019).

Conclusion

Parkinson’s Disease is an idiopathic disorder that arises from the degeneration of the dopamine-producing neurons within the central nervous system. The uncertainty behind the pathogenesis of PD has led to increased research into the etiology of PD and the association of potential genetic and environmental risk factors that could lead to the degeneration of these neurons. So far, aging has been identified as the only definitive risk factor in the development of Parkinson’s disease. Though there is no cure for PD, treatment therapies are directed toward the management of symptoms in order to make individuals living with the disorder more comfortable and capable in performing normal daily tasks. Future direction is aimed towards the use of new technologies associated with VR therapy and, hopefully, the use of iPSCs in regeneration of damaged neurons in PD patients.

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