The Introduction Of Parkinsons Disease Biology Essay

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In 1817, a British apothecary James Parkinson, published an essay: An Essay on the Shaking Palsy reporting 6 cases of paralysis agitans and described the symptoms and how the disease evolves over time, which awarded him by naming the disease bearing his name [1].

Attributed to the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), Parkinson's disease (PD) is a chronic age-related central nervous system disorder due to progressive neurodegeneration [2-4].

Movement-related symptoms such as tremor, rigidity, slowness of voluntary movement, postural instability, akinesia, gait and balance problem, dysarthria and dysphagia appear as PD progresses over time [5]. Suffering from the disease for more than ten years, non-motor symptoms like cognitive decline, dementia and sleep-wake cycle dysregulation may also occur.

Although some atypical cases (10%) are ascribed to heritable genetic mutations, most cases of Parkinson's disease are still sporadic [6]. The pathology of the disease is characterized by the selective death of dopaminergic neurons in the substantia nigra pars compacta, along with the abnormal intracellular proteinaceous aggregates called Lewy bodies (LBs) and Lewy neurite (LNs) which serve as hallmarks of Parkinson's disease. PD brain predisposes even young cells to form Lewy bodies.

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Neither cell loss nor Lewy bodies are respectively sufficient for PD diagnosis, the investigation of both of them, however, throws light upon the disease diagnosis. The distribution of the Lewy bodies throughout the Parkinsonian brain varies individually which is often directly linked with the expression and degree of the clinical symptoms of each individual.

Treatment that significantly decelerates the progression of the disease is still under research. Effective therapies, however, could relieve the early motor symptoms of the disease with dopamine replacement strategies, such as levodopa (L-Dopa) and dopamine agonists (DA- agonists) [2]. With the progressing of the disease and the continuing loss of dopaminergic, these drugs eventually lose efficiency at treating the symptoms and at the same time an involuntary writhing movement complication, dyskinesia occurs.

Several studies have demonstrated that insecticides, pesticides and herbicides exposure such as rotenone and paraquat, which elicit neurodegenerative phenotypes can contribute to PD [7-9]. Derived from the roots of various plants, Rotenone is an organic compound that used to eradicate nuisance fish and insects population. Being transported into the brain very rapidly, rotenone is also a classical, well-characterized and high affinity specific inhibitor of mitochondrial NADH dehydrogenase (complex I), one of the key enzymes complexes of the inner mitochondrial membrane oxidative phosphorylation takes place [10, 11]. Independent from the dopamine transporter for access to the cytoplasm of dopaminergic neuron, Rotenone crosses biological membranes easily due to its hydrophobicity [12, 13]. Symptoms of parkinsonism such as bradykinesia and rigidity appeares from animals after Rotenone infusing. Flexed posture and typical paralysis of advanced PD could also be found from seriously affected rats, showing chronic, systemic rotenone infusion recapitulated the anatomical, biochemical, pathological and behavioral features of PD [14]

Despite the fact that Rotenone has been linked with PD, it treated as a new method for selective nigrostriatal damage is still controversial. On the one hand, rotenone has been shown to lead to selective dopaminergic cell death in vivo: selective nigrostriatal dopaminergic degeneration was reported in rotenone infused intravenously or subcutaneously rat, although rotenone also induced degeneration of non-dopaminergic neurons in both the basal ganglia and the brainstem [12, 15, 16]. On the other hand, as for in vitro models, it was reported that dopaminergic neurons have higher sensitivity to rotenone-induced toxicity than other neuronal cells [17-19], but non-dopaminergic neurons were reduced by rotenone in primary mesencephalic culture as well [20-22].

1.2 The Introduction of α-Synuclein

1.2.1 Parkinson's disease caused by α-Synuclein

The protein α-synuclein, encoded by the α-synuclein gene (SNCA), is a small presynaptic phosphoprotein with 140 amino acids [6], extensively localizes in the nucleus of mammalian brain neuron [3, 23]. As an unstructured soluble protein normally, α-synuclein was found to be misfolded which aggregates to form insoluble fibrils as a major component of Lewy bodies [3, 4, 24]. The dysfunction finally results in dopaminergic neuronal death and associated with both sporadic and familial pathogenesis of several neurodegenerative diseases, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

The missense mutations or overexpression in α-Synuclein (i.e.: A53T, A30P, E46K and gene triplication) were reported to result in cytotoxicity, which causes direct cell loss and maybe dominant inherited PD [4, 23, 25]. A53T mutation was the first clear report that a Mendelian gene could be a cause of PD [24].

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The phenomenon that α-synuclein is closely related to Parkinson's disease is widely reported, while the mechanism of α-synuclein has not been clearly understood yet. Although a molecular study in 2008 suggests α-synuclein exists as a mix of unstructured, alpha-helix, and beta-sheet-rich conformers in equilibrium, there is considerable uncertainty on the aggregation mechanism of α-synuclein remains [26].

1.2.2 Cytotoxicity of α-Synuclein

The expression of α-synuclein negatively impacts yeast cells (Saccharomyces cerevisiae) in growing and stationary phases. It also has been shown to effect invertebrate model animals as well, Drosophila melanogaster and Caenorhabditis elegans, when the introduction of high level production of mutant forms or increase production of α-synuclein damages dopaminergic neuron cells in vivo and in vitro have also been reported. All the three model systems showed negative impact on cells with presence of α-synuclein in the organisms where it's normally not present. Additionally cell trauma and death appears with the presence of high levels of α-synuclein or its mutant forms when produced in primary neurons of mammalian cell culture in vitro [24].

1.2.3 Reason for Cytotoxicity of α-Synuclein

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Figure Events in α-synuclein toxicity [24]

The major pathway for protein aggregation could be illustrated by the left panel of the figure show above. As a natively unfolded structure, monomeric α-synuclein can bind to membranes in form of α-helix, and these two forms transform with each other in equilibrium within the cell. The in vitro work further clarifies that unfolded monomer tends to aggregate into small oligomeric sheets which can be stabilized by -sheet-like interactions first followed by forming higher molecular weight insoluble fibrils. The accumulation of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. Both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) where mainly macroautophagy and chaperoninen mediated autophagy have been suggested to contribute to α-synuclein turnover.  The presence of ubiquitin (shown as a black spot ) in Lewy bodies is believed to be part of a secondary process of accumulation possibly due to increased unfolding of α-synuclein which may enhance deposition in the growing Lewy body. The proposed cellular target for toxicity pertaining to α-synuclein, including ER-Golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery are clarified by the right panel of the figure above [24].

Although it is widely acknowledged that α-synuclein is a cytoplasmic protein that exerts its pathogenic effects in the cytoplasm of the cells, α-synuclein oligomer had been consistently detected in human cerebrospinal fluid (CSF) and blood plasma not only in diseased individuals but also those healthy. Moreover, α-synuclein was also demonstrated be released into the extracellular media by exocytosis and internalized into cells, implying that α-synuclein may not only functional intracellularly [23].

In α-synuclein transgenic models, α-synuclein aggregation is always related to neuronal degeneration either by loss of function or death [25]. Acknowledged from several imaging techniques, in the context of a living cells α-synuclein can form small oligomers, which may be associated with cytotoxicity. The formation of α-synuclein oligomers is linked to cell membrane damage and result in dysfunction of multiple cellular systems.

Since α-synuclein also may an important role in mediating both mitochondrial function and damage, cells which are α-synuclein overexpressing tend to display multiple markers of mitochondrial dysfunction, including increased protein oxidation, increased reactive oxygen species (ROS) production, loss of mitochondrial membrane potential and reduced Complex I activity [27-29]. Research shows that α-synuclein is localized in the inner membrane of mitochondria conditionally. The α-synuclein protein is highly expressed in the mitochondria in most parts of the brain where the cytosolic form is predominant. In addition, mitochondrial dysfunction is commonly observed with high levels of α-synuclein or its mutant forms, suggesting that α-synuclein have a negative impact on the biological function of mitochondria. Mitochondrial dysfunction is known to be a dominant contributor to PD due to the consistent observation of mitochondrial complex I ineffectiveness in PD patients. In this case, the background level of mitochondrial α-synuclein may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration. As before, α-synuclein causes mitochondrial dysfunction, which causes increased generation or ROX, which negatively impacts α-synuclein, thus causing increasing cycles of neuronal stress and impaired function, eventually leading to death the neuron and destruction of that nerve pathway. While α-synuclein is known to interact directly with lipid membrane, especially the vesicles [30]. It has been also been found that several genes that deal with metabolism of lipid play a role in α-synuclein toxicity by yeast genome screening. Lipid metabolism is common to both cellular and mitochondrial membranes and may bear closer examination. It has been reported that α-synuclein forms an extended helical structure on small unilamellar vesicles and is involved in vesicle trafficking by binding small vesicles. Indeed, there is growing evidence that α-synuclein is involved in normal protein trafficking at the Golgi and endoplasmic reticulum (ER) [31].

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In the normal brain, α-synuclein immunostaining reveals a diffuse pattern of reactivity throughout the neuropil that would be consistent with a predominantly synaptic localization. Immunostaining is using in the location study of α-synuclein. However, in PD brains, α-synuclein antibodies have extremely high sensitivity stain LBs and LNs. For the high sensitivity, α-synuclein staining is used more widely instead of the less specific staining by the dye eosin. Although it has been proved α-synuclein has a close relation with PD, it is demonstrated that increased production of some specific biological molecules, like heat shock proteins (Hsps) can prevent toxic effects of α-synuclein in yeast and in flies [32, 33].

1.3 The Introduction of Yeast

Yeast model is probably the simplest system used to illustrate the toxicity caused by α-synuclein expression. With the best-characterized eukaryotic genome, budding yeast (Saccharomyces cerevisiae) is regarded as the ideal species for rapid genetic interrogation [4]. Cell-autonomous mechanisms of neurodegeneration were also examined by using yeast as an interactome system not only due to its simpler and more fully-understood genome, but also because it is easy to analyze an eukaryotic organism given that the availability of genetic banks of diploid and haploid gene deletion screens [24]. As a powerful genetic tool, budding yeast is adopted to reveal protein misfolding processes underlying human diseases [34], including Huntington's disease [35, 36], prion disease [37], and amyotrophic lateral sclerosis [38, 39] as reported before where single gene deletion stain banks in diploid and haploid strains have proved central to elucidation of these various biological processes in yeast. Full understanding of these biological systems and processes in human cells and mammalian model animals obviously has lagged behind the understanding that has occurred in these powerful yeast systems.

Previous publications have already shown that the increasing α-synuclein expression could contribute to cell death in growing and stationary phase cultures [24]. As yeast is a unicellular with a scalable system, it enables high throughput genetic and small-molecule screens. Apart from the advantages we mentioned above, most important part is its genetic tractability which enables its DNA to be transformed quite easily, at the same time homologous recombination is efficient [39, 40]. This facilitates both the replacement of any gene with a mutant allele and the recovery of almost any mutation created in vivo [41]. These gene deletion "knock outs" of central biological processes (in haploid strains), such as DNA replication, are unfortunately lethal, but "conditional" or impaired systems may sometimes be constructed to partially examine some of the central or core processes.

It is nevertheless surprising that budding yeast is able to productively imitate some complex disease processes, such as those contribute to neurodegenerative. Thus yeast plays a non-substitutable role in initially understanding aspects of various neurodegenerative diseases. Major aspects of cellular pathology are captured by yeast models as first step and are providing novel gene-environment connections and therapeutic targets on an unprecedented scale through the use of high-throughput genetic based screens [41]. Two characteristics are required for the model systems to be applied for human disease research: the model has to be relevant to human disease and easy to be analyzed, which are possessed by yeast and enables yeast to be the best of choice in our research. The relevance can be ascribed to its conserved genome and cellular biology while the convenience for analysis can be related to its genetic tractability, scalability and shorter generation times [41].

The amenability to analysis can be explained by its easily transformed genome allowing for either the addition or deletion of genes through homologous recombination, grows in a highly reproducible and genetically stable way and short generation time [41, 42]. Genomic homology is a phenomenon reported by several articles. At least 60% of yeast genes are shown robust human homologues or at least one conserved domain with human genes statistically [41, 42]. In addition, a close yeast homologue can be found among more than 25% of known human disease genes [43, 44], which is explained partially by the conservation of many fundamental cell biological processes between yeast and mammalian cells [41].

Besides genome, the cellular protein additionally demonstrates high conservation of sequence and functional applications and more remotely their interactive partners. The first clue to the function of many higher eukaryotic genes can be provided by the homology to a yeast gene. Numerous cellular pathways of high relevance to neurodegenerative, such as protein folding, quality control and degradation, vesicular trafficking and fusion, apoptosis, mitochondria and oxidative stress and autophagy are conserved in yeast. The most common neurodegenerative diseases, (e.g.: Alzheimer's disease and Parkinson's disease) are ascribed to intracellular proteinacious aggregates. Protein misfolding, oligomerization and aggregation with neurodegeneration have been intimately associated by multiple lines of evidence. Thanks to the conservation of the cellular protein quality system, the study of these processes are readily studied in the yeast genetic systems [41].

In yeast, the same as in mammalian cells, the central organelle for the production of reactive oxygen species (ROS) which is heavily implicated in neurodegeneration are the mitochondria as mentioned previously. The fermentative growth ability of yeast allows for the analysis of mitochondrial defects that would be lethal in mammalian cells [41].

By adopting the yeast model, a conserved link between endoplasmic reticulum (ER)-Golgi traffic and α-synuclein toxicity has been established [34, 45]. The pathway proteins are translocated from the endoplasmic reticulum (ER) to the Golgi complex and then trafficked in vesicles to the plasma membrane, is of particular importance in neurons that need to transport proteins over long distances to nerve terminals and that release neurotransmitters by vesicular fusion [41]. Additionally, yeast is increasingly recognized as a model organism for the study of apoptosis as the basic molecular machinery executing cell death is phylogenetically conserved. In addition, yeast apoptotic death occurs in dependence of complex apoptotic scenarios such as mitochondrial fragmentation, cytochrome c release and cytoskeletal perturbations [46]. The conserved mechanisms of yeast cell death and survival are relevant to neural loss. Both apoptotic and non-apoptotic cell death mechanisms are implicated in neurodegeneration [41].

The genetic tractability and genomic stability endow the yeast a significant advantage over transformed or cancer derived immortal mammalian cell culture lines, and these characteristics are particularly necessary in a model system for initial screening for agents for therapeutic treatment of neurodegenerative diseases. Yeast phenotypes can be screened based on genome-wide deletion, reduced expression or overexpression libraries. Depending on whether a yeast homologue exists or not, one of two general approaches can be employed to imitate human disease in yeast. The human disease-related gene can be disrupted or overexpressed to determine the loss or gain of function phenotypes respectively with the presence of homologue in yeast [39, 40]. Clear yeast homologues exist for many genes associated with neurodegeneration. This modeling approach has already been proved to be highly productive [41].

1.4 The Introduction of High-throughput screening

Originated from natural product screening just for pharmaceutical, biological, biotechnological research and development 30 years ago, High-Throughput Screening (HTS) is a scientific method of experimentation particularly used in the process of drug discovery nowadays. The destination is to obtain a high efficiency by conducting copious of parallel biological experiments or tests in parallel using automation and miniaturization techniques, with the use of robotics, liquid handling devices, sensitive detectors, and data processing and control software [47-49]. A great many experiments of genetic, pharmacological, and chemical assays in a much shorter duration can be realized by High-Throughput Screening, through which active compounds, antibodies or genes which modulate a particular biomolecular pathway can be rapidly identified and the role of the interaction of a particular biochemical process in biology can be understood.

High-throughput screening is a key link in the chain comprising the industrialized drug discovery paradigm. In this procedure, as long as a compound interacts with a target in a productive way, it then passes the first obstacle to become a drug. Compounds that fail the primary screen go back into the library for the further screen against other targets.

A compound with a desired result in a high-throughput screening usually called hits, which are collected for further testing to go through effect determination.

1.5 Blueberry and Parkinson's Disease

Numerous studies suggested that a decreased antioxidant/oxidative/inflammatory stress balance plays the most important role in mediating the deleterious effects of aging on behavior and neuronal function [50]. From epidemiological evidence, it is indicated that antioxidant supplementation provide neuroprotection against age-related neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease [51]. Experimental evidence obtained from animal model studies links consumption of specific fruits and vegetables to reduced age- and disease-related neurodegeneration. Higher levels of antioxidant activity may be involved in the putative protective effects. Blueberries (BBs) contain the foods highest levels of polyphenolic flavonoids [52].

A 20-year investigation revealed that greater intakes of berries were strongly associated with a lower risk of PD and blueberries were proved to be neuroprotective in primary midbrain cultures. Administration of berry fruits, which contain flavonoid revealed protective effects on dopamine neurons from oxidative damage and apoptosis and inhibit formation of α-synuclein fibrils [53], which clearly clarified that anthocyanins have a protective effect on PD in terms of epidemiology.

A large quantity of studies in the past 10 years have revealed that polyphenols have the activity in preventing or reducing the deleterious effects of oxygen derived free radicals associated with several chronic and stress related human and animal diseases both in vitro and in vivo. Flavonoids are the largest group of polyphenols, which is mainly divided into anthocyanins, glycosylated derivative of anthocyanidin [54].