Parkinson’s progressive muscular dysfunction (bradykinesia) which is a

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Parkinson’s progressive muscular dysfunction (bradykinesia) which is a

Parkinson’s disease is a similar illness which primarily affects one’s ability to move, communicate and organise thoughts in a coherent manner. Despite that Parkinsonism is considered idiopathic, numerous genetic and environmental factors can increase an individual’s susceptibility to this disease. In the genomes of patients displaying aspects of Parkinsonism there are usually mutations in the gene that codes for alpha-synuclein; a protein which aids the formation Lewy bodies that develop inside nerves. Furthermore, genetic mutations in the gene UCH-L1 also degrade the ability of lysosomes to hydrolyse excess alpha-synuclein through reducing the production of cathepsin B; a protease which plays an important role in intracellular proteolysis.The onset of Parkinson’s is usually followed by progressive muscular dysfunction (bradykinesia) which is a direct result of a decrease in production of dopamine. As nigostriatal dopaminergic neurons die within the brainstem, input signals and output signals become uncoordinated which accelerates the loss of control of muscular contraction as the disease progresses. The main treatment for bradykinesia and dopaminergic death is through oral delivery of L-DOPA and dopamine-receptor agonist drugs. However, I argue that these two medicines are ineffective at preventing further neuronal death and decline which is vital to reverse the effects of neurodegeneration. I propose that an effective stem cell therapy for this disease should not only look to delay the formation of alpha-synuclein, but aims to stimulate dopaminergic neurogenesis to provide therapeutic relief for bradykinesia.I am intrigued in one study which explored this further by programming embryonic stem cells to generate and maintain the levels of dopaminergic neurons within the striatum. This was achieved through suspending embryonic stem cell colonies in a growth medium primarily consisting of fibroblast growth factor 8, which helped to stimulate the specialisation of the stem cells into neuroepithelial cells. The stem cells were then exposed to neurotrophic factors, including FGF2 and the signalling protein ‘sonic hedgehog’, to initiate a dopaminergic ventral tegmental function. After PCR and immunocytochemical analysis to confirm the culture was successful, they were injected into the medial forebrain bundles of 12 lesioned model rodents, programmed to secrete dopamine in response to continual neuronal depolarisation. With regard for their grafting procedure, I believe that it was very effective when one considers that the stem cell colony had multiplied in size with an average of 1,273 dopaminergic TH+ neurons per graft (see Fig.4). However, it is important to evaluate if the stem cells resultantly improved the rodents’ ability to coordinate movement. In fact, I can clearly infer from the amphetamine-induced rotation tests that the rats transplanted with embryonic stem cells possessed a much higher degree of functional recovery when compared to a control group of 5 rats (see Fig.5). Although, in criticism of this I think that such a small sample size should not be thought of as fully representative of the effects of this therapy. One must also remain aware that cognitive improvement was only detected 20 weeks post-transplant which may not be practically feasible for most patients. Considering long-term prognosis, it is vital that teratoma formation is not be induced. In this study, tumour growth was minimised through eliminating any differentiated stem cells of non-neural lineage before the final culture stage. This checkpoint prevented any ectodermal or mesodermal cells proliferating within the sample. The detection of neuronal differentiation without any indication of tumorigenesis, alongside the results from the rotation tests, strongly encourages further investigation into the potential of dopaminergic neuronal therapy.To evaluate the viability of a stem cell therapy, each transplant is required to be trialled on a transgenic model. I regard the Papio anubis baboon as particularly reliable for this purpose as their brains have very similar microvasculature when compared to a human brain. More importantly for Parkinson’s disease, they share the same pattern of dopaminergic loss due to natural age progression. I believe that a cell culture extracted from a Papio anubis baboon may offer an accurate indication of the longer-lasting effects of a therapy, including potential negative side-effects such as tumorigenesis or rejection. In one study, Papio anubis-derived iPs cells were exposed to a spectra of developmental morphogens; including sonic hedgehog, dorsomorphin, brain derived neurotrophic factor and glial derived neurotrophic factor. Over 118 days, these morphogens manipulated the cell specialisation process to mature the iPs cells into a sample of induced pluripotent-derived dopaminergic neurons (see Fig.6). To evaluate this study, I must first consider if the iPs cell derived-neurons displayed the correct biomarkers of an endogenous dopaminergic neuron. By the end of the 50-day maturation cycle, 74.7% of the iPs-derived cells expressed Beta III-Tubulin and 55.1% of all cells expressed both. While the presence of Beta III-Tubulin is widely associated with succesful neural development from multipotent progenitors, I am aware of its link with clear cell adenocarcinomas. As a result of this detection, I remain wary of of tumour formation within a patient when evaluating the extent of utility gained from this stem cell lineage.One must also acknowledge the electroconductive abilities of the neurons to evaluate their suitability as a key constituent of the dopaminergic network. This was achieved in the study by generating a minor electrical perturbation of the cell membrane and then measuring the response by electrophysiological detection. In a sample of 11 neurons, all the cells exhibited a remarkable ability of being able to regulate the rhythm of action potentials with frequencies ranging from 2 Hertz up to 10 Hertz. In my opinion, this range of frequencies (combined with an average action potential spike width of 4.98 milliseconds) indicates that these neurons had largely established the essential properties of a dopaminergic neuron. Interestingly, electrophysiological analysis of one neuron illustrated that by increasing the intensity of the depolarising current the frequency of action potential firing proportionately increased. However, two other iPs-derived neurons could not exceed an action potential frequency of 22 Hertz, and sometimes displayed spike-frequency adaptation (see Fig.7). Conclusively, these results illustrate how stem cell-derived dopaminergic neurons can be programmed to largely exhibit both the genomic expression and neuronal functionality as desired, highlighting the Papio anubis baboon as a viable source of transplant-suitable neurons. This is primarily based on the detection of both the TH+ and Beta-III Tubulin biomarkers in an almost identical pattern as an endogenous dopaminergic neuron. Moreover, most of the iPs cell-derived neurons also displayed a capacity to regulate their action potential frequency when stimulated by membranous electrical perturbation. Therefore, these results lead me to think that they are capable of being a part of a complete electrical system.However, it is important to be critical of spike frequency adaptation and over-expression of Beta III-Tubulin. Spike frequency adaptation could even lead to the resultant dysfunction of voltage-gated ion channels, in addition to difficulties regarding the self-regulation of action potential firing. Therefore to improve this study, I believe that more research must be conducted into how these inconsistent electrical anomalies can be minimised in order for this therapy to be viewed a viable course of treatment.



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