Running head : PARKINSON ’ S DISEASE 1 Parkinson ’ s Disease : Molecular Mechanisms and Treatments

Parkinson’s disease is a motor system disorder that is caused primarily by the loss of dopamine-producing brain cells. The most affected brain structure is the pars compacta of the substantia nigra. This area of the brain is essential to the control of voluntary movement, and so its impairment leads to symptoms such as tremors, rigidity, and impaired balance. The neuronal protein alpha-synuclein has been shown to be heavily involved in the pathogenesis of the disease at the cellular level. The currently available treatments for PD mainly target dopamine regulation, and there been no cure developed for the disease at present. New treatments must be explored by an evaluation and synthesis of the current research and should be adjusted for each patient individually. PARKINSON’S DISEASE 4 Parkinson’s Disease: Molecular Mechanisms and Treatments The biological mechanisms and treatment pathways for Parkinson’s disease (PD) are slowly being uncovered. The molecular basis of the disease and its various causes are the fundamental starting point of this process. In order to understand how the symptoms of Parkinson’s present and how they can be targeted, it is important to determine how the molecular pathology affects the PD patient on a macroscopic level. The currently available treatments for PD are continually being improved and expanded upon since there has been no cure developed for the disease at present. Possible new avenues for treatment must be explored by an evaluation and synthesis of the current research and therapy options available. Introduction and Justification of Research Approach Parkinson’s disease is a disorder of the motor system. It is caused primarily by the loss of dopamine-producing brain cells. There are four main symptoms of PD: tremors, rigidity, bradykinesia, and impaired balance and coordination. All of these symptoms have a molecularand cellular-level basis, much of which has yet to be completely revealed. The most notable brain structure damaged in Parkinson’s disease is the pars compacta, a part of the substantia nigra. The neurons in this area of the brain are part of a pathway for the control of voluntary movement and they use the neurotransmitter dopamine. When dopamine is not present at normal levels, as in the case of PD, this causes an individual’s ability to coordinate movement to be significantly impeded. Because of the diversity and variability inherent in the clinical manifestation of Parkinson’s disease, the diagnoses are often broadened into a spectrum of disorders known as parkinsonisms. Furthermore, the diagnostic criteria of the disease have changed PARKINSON’S DISEASE 5 over time. These criteria have been developed based on both the symptoms that are observed in Parkinson’s disease patients and their underlying molecular causes. Confirmation of the presence of the disease is sometimes not apparent until the patient has died and a postmortem examination has been made. Although strict criteria have been developed and accepted for the diagnosis of Parkinson’s disease, there still exist certain gray areas in diagnostics. Certain specifics of the disease currently qualify as parkinsonisms, but these aspects deserve attention due to their relevancy and correlation to the purported Parkinson’s disease. Parkinson’s disease has a variety of genetic sources. However, several epigenetic causal factors have been identified as well. There is evidence that one of these factors is an increase in the formation of reactive oxygen species. These reactive species can originate both inside and outside the mitochondria (Zhou, Huang, & Przedborski, 2008). Another causal factor may be toxins in the environment. For example, a contaminant found in some illegal drugs in the 1980s, methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), was found to lead to the development of parkinsonism in drug users. MPTP is soluble in lipids and so it is able to cross the blood-brain barrier. The toxin is then modified inside the brain and is recognized by the dopamine transporter. This is extremely detrimental to the neurons because the molecule binds to NADH dehydrogenase and essentially terminates the electron transport chain. Starved for ATP, these cells shortly die. Besides the environmental causes of Parkinson’s and parkinsonisms, there are several common genetic mutations that can occur that lead to the disease. Possible sites for a mutation include PARK1, the gene that codes for α-synuclein, and PARK2 through PARKINSON’S DISEASE 6 PARK12. There is strong evidence that α-synuclein plays a principal role in the development of Parkinson’s disease. However, due to the delicate complexity of PD, there are likely to be many different important proteins involved in the process and these principal proteins may differ in the extent of their role from patient to patient. Each of the gene products transcribed from the PARK family of genetic mutations has a distinctly different effect on the operation of the neuron in which it is produced. In order to study how each of these proteins leads to the overall expression of common Parkinson’s disease symptoms in a patient, their normal function must be elucidated. Knowledge about the normal functioning of these proteins can be just as important as an understanding of their pathogenic behavior. As research has shown, much of the pathology of Parkinson’s disease must be explained not only by the loss of function of a protein or brain region, but also by a gain of function that is detrimental to the normal working of the cell. The immediate goal of the current research being conducted on Parkinson’s disease is to provide a description of how each specific molecular pathway works to affect the Parkinson’s disease patient on a macroscopic level. The most prominent questions that today’s researchers seek to answer are problems such as these: how does the aggregation of the protein α-synuclein impair the PD patient’s cognitive and motor skills? What specific symptoms are made manifest by this molecular abnormality? Parallels will be drawn between each of the causal factors of the disease and their respective expressions in the patient’s physiology. The currently available treatments for Parkinson’s disease are continually being accumulated and modified as new research reveals target areas for development. The PARKINSON’S DISEASE 7 disease was originally thought to have been acquired de novo due to environmental factors or toxins. However, within the last ten years or so, increasing evidence for the genetic basis of the disease has surfaced. Understanding these mutations and inherited traits better will open countless avenues for treatment, from drug development to gene therapy. Each of the molecular mechanisms of the disease presents a unique opportunity for management of the symptoms it produces. The experiments described in this review investigate how and where each pathogenic molecular pathway may be intercepted, perhaps with a new drug, that would restore the natural biological process or at least mitigate the effects of the disease. Noting the diversity of Parkinson’s disease cases, it is probable that the conclusion of this problem will be a multifaceted one. It is likely that the various mechanisms of the disease, while there will be many parallels, will also differ substantially. Because of this, a multiplicity of treatments will be proposed to fit each distinct case in a uniquely appropriate way. Alpha-synuclein and the Pathology of Parkinson’s Disease Current Parkinson’s Disease Research Techniques The biological and chemical mechanisms regarding abnormal protein aggregation in the brain of Parkinson’s disease (PD) patients is forefront in the developments of Parkinson’s disease research. The molecular basis of the disease and its various causes have been investigated and analyzed, according to the results of previous experiments. Extensive Parkinson’s disease research is also conducted at hundreds of other labs and institutions across the world, including the National Institutes of Health (NIH). This research seeks to explain how these mechanisms correlate with the most common treatment pathway of the PARKINSON’S DISEASE 8 disease. Last, the effectiveness of L-DOPA as a treatment for Parkinson’s disease treatment will be analyzed. Molecular Techniques Reveal the Cellular and Molecular Mechanisms Parkinson’s disease has a variety of genetic and epigenetic sources. These sources have been discovered and analyzed by a plethora of methods, including NMR, spectrophotometry, genetic techniques, proteomics, neuroproteomics, analysis of enzyme kinetics, and pharmacokinetics. Specific results from selected techniques will be described throughout the discussion in order to analyze further the mechanism of protein aggregation in Parkinson’s disease. One of the most important sources for Parkinson’s disease pathology appears to be the abnormal aggregation of a protein called α-synuclein in the brain. Alpha-synuclein has only primary structure, and there is generally no secondary or tertiary structure determined by its amino acid sequence. Many proteins that remain in an unfolded state serve as chaperones in the cell and can aid in the folding of new proteins (Irvine, ElAgnaf, Shankar, & Walsh, 2008). However, NMR spectroscopy has revealed that when α-synuclein is bound to a lipid or micelle surface, the protein will adapt a secondary structure: a right-handed alpha helix interrupted by a single break (Bussell & Eliezer,