My interest in researching Parkinson’s Disease hits close to home as I have two grandparents with the disease. My paternal grandmother was diagnosed in 2014 but was symptomatic for about a year prior to her diagnosis, and my maternal grandfather was just diagnosed this September. My grandmother’s condition is now classified as late-stage, while my grandfather has yet to start treatment. In writing this paper I hope to better understand the physiological changes that my grandparents’ bodies are undergoing as well as the progression of their conditions still on the horizon.
I will cover the background and basic anatomy of Parkinson’s, examine the underlying physiological mechanisms behind the disease, and examine recent research and future research directions. Parkinson’s Disease falls under the umbrella of neurodegenerative disorders. This group is a characterization of chronic diseases caused by loss of neurons in the brain and spinal cord that lead to dysfunction and eventually disability (2018).
Neurodegenerative disorders include but are not limited to Alzheimer’s disease and other dementias, Prion disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy. Parkinson’s Disease is the second most common among this group following Alzheimer’s (2017) (Gibrat, et al., 2009). After the age of 65, 1%-2% of the international population is affected by Parkinson’s Disease, affecting approximately one million people in the United States and ten million worldwide, which highlights the prevalence of the disease (Gibrat, et al., 2009).
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The cause of the disease remains largely unknown, however research points to a combination of both environmental and genetic factors (n.d.). Neurodegenerative disorders often share overlap in symptoms, especially early onset symptoms which include tremors, memory problems, hallucinations, movement and balance problems, among many others. While Parkinson’s Disease can include memory problems and hallucinations, symptoms are predominantly motor impairments consisting of tremors, bradykinesia or slowness of movement, akinesia or absence of movement, rigidity of the limbs, worsening speech, postural instability and gait and balance problems.
Parkinson’s symptoms typically develop gradually over years, but the rate at which they progress vary greatly for each individual. There is not a definitive test for Parkinson’s Disease, rather a clinical diagnosis based on the culmination of these many symptoms (2018) (Masliah, 2018). Research suggests the underlying pathology of the disease is primarily caused by dopaminergic neurons undergoing a progressive degeneration and premature death, which begins in the pars compacta of the substantia nigra (Gibrat, et al., 2009). The substantia nigra is a large dark nucleus located in the midbrain, but with regard to function considered a part of the basal ganglia due to its many connections in the brain stem. The substantia nigra is split into two elements: the pars compacta and the pars reticulata.
In Parkinson’s the element that is affected is the pars compacta because that is where the cell bodies of the dopaminergic neurons exist (Webb, 2017). The dark color of the substantia nigra comes from the black pigmentation of the dopaminergic neurons, and as the dopaminergic neurons die, the dark color is lost which can be visibly seen in a postmortem examination of the brain stem, which is represented in Fig. 2 below (Tuite, 2016). An aspect of Parkinson’s that is undeniably related to its pathogenesis is the presence of α-synuclein proteins in the form of deposits or clumps. The clustering of α-synuclein proteins form Lewy bodies and Lewy neurites, which are considered to be a trademark of the disease as these inclusions are observed in the brains of nearly all Parkinson’s patients (Dehay, et al., 2015).
The presence of the α-synuclein protein is not abnormal, rather the aggregation of the protein is. Lewy bodies are not exclusive to Parkinson’s, in fact other diseases possess these protein deposits as well. Diseases with the presence of Lewy bodies are considered to be part of the synucleinopathies family which encompasses Dementia with Lewy bodies and Multiple System Atrophy. Interestingly, while most Parkinson’s patients have these Lewy bodies that does not indicate that they have dementia with Lewy bodies as well, although there is definite overlap of the two diseases where some individuals have both (Longhena, et al., 2017).
To better understand why the aggregation of α-synuclein proteins is problematic, let’s consider what is understood about their appropriate function at the dopamine synapse. While the complete function of this α-synuclein protein is not fully understood, it is apparent that the protein is abundant in the presynaptic terminals of both the brain and peripheral nervous system and aids in the function of synaptic vesicles, the site where neurotransmitters are stored and released. Similar to other neurotransmitters, dopamine is responsible for transmitting chemical impulses between nerve cells across this synapse.
While responsible for many pathways in the human body, it is also used in muscle control. Evidence shows that the presence of the α-synuclein protein is heightened within dopaminergic neuron synapses, where the protein aids in modulating dopamine release via the dopamine transporter. In individuals with Parkinson’s the formation of α-synuclein protein at the dopaminergic neurons are atypical and take on a mis-folded composition which compromises the dopaminergic neuron function. This diminishes dopamine production, reducing cell-to-cell transmission and leading to the deterioration of proper dopamine function throughout the body (Longhena, et al., 2017).
While the depletion of dopamine is primarily responsible for the symptoms of Parkinson’s Disease, severe dopamine loss can begin to affect other basal ganglia pathways, including altered function of other basal ganglia neurotransmitters such as glutamate, GABA, and serotonin (Gasparini et al., 2013). Improper dopamine function in the body hinders a important aspect of the motor pathway. In appropriate function, the basal ganglia expend a consistent inhibitory influence to mediate motor systems and prevent action at unwanted times. When an individual makes a decision to perform a specific action, that inhibitory influence is lifted on the appropriate motor system, thus allowing activation.
With dopamine responsible for the constant inhibition of movement, higher levels of dopamine lead to increased motor function. Parkinson’s individuals’ decreased dopamine levels demand higher exertion to release the activation for the desired motor system and perform an action. The resulting effect of inadequate levels of dopamine between the basal ganglia and substantia nigra leads to a reduction in smooth and balanced muscle coordination, including tremors, bradykinesia, and akinesia (Obeso, et al., 2008).
While the understanding of the pathogenesis of Parkinson’s is becoming increasingly understood, the mechanisms behind acquiring the disease, loss and degeneration of dopaminergic neurons, and the formation and significance of α-synuclein protein inclusions remain largely unknown. The slow traction in understanding the disease can be discouraging, however Parkinson’s Disease researchers have already discovered several genetic markers linked to to the disease, including mutations of the LRRK2, PARK7, PINK1, PRKN, or SNCA gene. Despite the genetic connections, only 15% of people diagnosed have a family history of Parkinson’s (2012).
Future research will likely include genome-wide association studies (GWAS) which scan large sample sizes of genetic information to find associations between a person’s genetic makeup and the risk factors associated with acquiring the disease (n.d.). Another promising future research and treatment direction is the targeting of α-synuclein proteins. Since the presence of these protein inclusions are an undeniable feature of the disease, it’s a fair direction to pursue. In fact, there have been experimental trials targeting α-synuclein toxicity with encouraging preclinical outcomes.
The variation of the α-synuclein forms among patients require further examination and understanding from a clinicopathological standpoint. On that note, establishing biomarkers for α-synuclein pathology would be an important next step in tracking over time which could allow for future clinical trials to be tracked in relation to biomarkers (Dehay, et al., 2015). Treatment options for Parkinson include both medication and surgical therapy. While there are many medications available for treatment, they can only reduce symptoms and none exist that can reverse the effects of the disease.
Treatment regimens are often tailored to each specific patient as the effects and symptoms of the disease vary widely for each individual. The most popular treatment among patients is the medication Levodopa, or L-dopa (2018). Due to the extremely selective permeability of the blood-brain barrier, water-soluble molecules without transporters cannot permeate into the brain. This makes it very difficult to formulate medications that target the brain. Dopamine is unable to cross the barrier when administered via pills or injections, so L-dopa is prescribed instead. L-dopa the precursor to dopamine and is transported across the blood-brain barrier via an amino acid transporter.
Once in the interstitial fluid, L-dopa is converted into dopamine (Silverthorn, et al., 2007). Unfortunately, L-dopa loses its effectiveness over time. This loss in effectiveness is not because patients build a tolerance, but because the medication causes widespread changes in DNA methylation, altered gene activity in cells in response to external environmental factors. This change in gene activity leads to gross involuntary movements, often after a few years of relying on the medication. Once this reaction starts, there is no way to stop it without completely discontinuing L-dopa medication (Kegel, 2016). The unsatisfying conclusion is that much of Parkinson’s Disease understanding, pathogenesis and pathophysiology are yet to be uncovered.
It is clear that more work is needed although there is promising research on the horizon, and a variety of treatment options and strategies that can slow the progression of the disease. Several strategies could be to replace or repair lost or damaged brain cells, control and manage particular symptoms, and/or diagnose Parkinson’s at the earliest possible stage. With one million Parkinson’s Disease individuals in the United States, and ten million worldwide, the disease is being aggressively research every day, which gives hope that life changing advancements will be available in the near future.
