About this sample
About this sample
Words: 1870 |
10 min read
Published: Jan 21, 2020
Words: 1870|Pages: 4|10 min read
Neurodegenerative diseases are becoming more prominent in today’s world. Be it due to life style changes or due to inheritance… the number of cases in this domain of medicine are on constant rise. The most prevalent of them are Alzheimer’s dementia and Huntington’s Chorea or Huntington’s disease. While Alzheimer’s disease is mostly associated with loss of memory and loss of logical thinking… Huntington’s disease has more physical and psychological implications all together. The next session briefly discusses about the causes and symptoms of Huntington’s disease and some statistics.
Introduction to Huntington’s Disease: Huntington’s disease is a neurodegenerative disorder that is caused due to an autosomal dominant mutation that results to disruption of a protein called Huntingtin protein. The mutated gene passed down the generations. It is a late on-set disease with symptoms appearing in Only a 10% of all the cases are seen due to a mutation in the same individual. This particular mutation causes the expansion of the poly glutamine[Q] repeat in the first exon of the Huntingtin protein. Huntingtin protein’s exact purpose is still not known; it appears to have some vital activity in the nerve cells. It was reported that the Huntingtin protein interacts with many proteins that are found only in the human brain. So it is apt that the disrupted form of protein has huge deleterious effects on the neurological function of the body. With more glutamine repeats, the protein starts to aggregate and form a fibrillary structure that resembles the β- amyloid fibrils in the disease of Alzheimer’s. The research has shown that it is not only the length of the poly Q repeat that actually governs the amyloid formation but also affected the concentration of the amyloids at the given point of time.
Yeast is most often used as a model for studying most of the neurodegenerative disorders for the following reasons:· It has a very short generation time (80 minutes) and shares 50% similarity with humans at genome level.
Yeast as a model for study of Neurodegenerative diseases: Even though Yeast doesn’t possess a nervous system, all the pathways that form the foundation for the nervous system and various disease that impact the nervous system, such as the mitochondrial and proteasomal dysfunction, transcriptional regulation, trafficking problems. If an analog for the human disease causing gene is present in Yeast directly, it makes the study much more easy. Even if an analog is not available, it is very easy to study the given human gene by using heterologous expression in the yeast cells. Diseases like Alzheimer’s also fall under the category of diseases that are caused due to protein misfolding. The Amyloid Hypothesis that refers to formation of aggregate proteins in a fibrillary manner due to aberrant interaction of proteins was actually formulated after rigorous studies on Alzheimer’s disease. So it is evident that some of these serious neurodegenerative disorders are also caused due to protein misfolding; especially due to a mutation in the given protein. The next session refers to the role of Yeast in studying the Alzheimer’s disease.
Role of Yeast in studying the Alzheimer’s disease: Alzheimer’s Disease or AD is one of the most lethal neurodegenerative diseases which is on a raise in the current society. The symptoms of this disease often vary but include the characteristic dementia, cognitive dysfunction and severe behavioural changes. Most of the cases doesn’t have a clear causative agent or gene but in some fraction of the affected individuals, autosomal dominant mutation is seen in the Amyloid Precursor Protein (APP), presenilin-1 and 2 (PSEN-1/PSEN-2). The hallmark of this disease is the presence of tangled fibrils inside the neurons and plaques of amyloids in the extracellular region. The main component of these plaques are Beta peptides, that are result of the proteolytic cleavage of the defective APP by sequential action of β and γ secretase. This cleaves the protein within the Aβ sequence. To study this particular gene in Yeast scientists cloned the Human APP gene and successfully expressed it, only to find out that the gene responsible for the expression of β and γ secretase is absent in yeast. Though there is a close relative to them in the form of aspartyl protease (α- secretase like activity), it was not so useful. So scientists used the heterologous recombination process and demonstrated the expression of γ secretase successfully by expressing its four components. The Aβ42 aggregation was also successfully studied in-vivo by taking advantage of the SUP35 gene that encodes for the termination of transcription and undergoes spontaneous changes and losses its function. The new Yeast models also showed the involvement of HSR genes. (Miller-Fleming, Giorgini, and Outeiro 2008)
Role of Yeast in studying Parkinson’s disease: Parkinson’s Disease is characterised by the muscle rigidity, instability in posture and tremors while resting. Concentric cytoplasmic inclusions composed of Hyaline, which are termed as Lewis Bodies (LB) are spotted by histological analysis. They contain the protein α-Synuclein and some subunits of molecular chaperones. The actual proposed theory was that these LB are developed by the neurons as a protective mechanism against the accumulation of pathogenic intermediates. The disease has both familial inheritance and sporadic occurrence. The study of PD using yeast as a model started by cloning the wild type α-syn and the other one with a mutation at 53 from AtoT (A53T). The formation of inclusion bodies was dependent upon the concentration. It was seen that both the wild type and mutant α-syn are directed to the plasma membrane and also caused Endoplasmic Reticulum stress. It also inhibited Phospholipase-D, and then function of endocytosis is impaired, which included the formation of lipid droplets. (Ciechanover and Kwon 2015)
Amyloids and their effects on cellular integrity: Various organisms have developed mechanisms to clear misfolded proteins from their systems very efficiently. The processes like ubiquitination and sumoylation, have improved in their efficiency over the course of evolution. But still, there are some cases where the protein degradation pathways are rendered useless. One such case is amyloid formation. It might happen as an aftermath of various mutations. The misfolded proteins that are not cleared by cellular mechanisms, form insoluble aggregates called as Inclusion-bodies (IB)s. These interrupt the normal functioning of the cells in many ways and cause a lot of damage. In most of the organ systems and organs, all the old cells die and are replenished by the new cells. Muscular and Nervous system are exemptions from this phenomenon. The cells in these two systems are not replaced so often. If the cells are being recycled regularly, this protein aggregation may not have so much of deleterious effect on the human body. If this happens in a neuronal cell, then it is of a major concern, for they cannot be recycled and replenished. That is the precise reason, why most of the amyloid forming diseases are often neurodegenerative diseases. Even though there is no clear evidence of the mechanism by which these amyloids cause neurotoxicity, there are some potential hypotheses proposed in recent years. Some state that the formation of amyloids halts the Ubiquitin-mediated protein degradation, because the proteasomes are stuck in the thick bundles of amyloids. It was also observed that the formation of amyloid impacts several transcriptional processes, because the transcriptional factors (32, 45, 46) have an abnormal-affinity to the IBs. (Meriin et al. 2003).
Role of Yeast in studying Huntington’s Disease: Yeast is said to be one of the most useful models for the study of any amyloid aggregation disease, especially Huntington’s chorea. The first Yeast-based model for the study of Huntington’s was reported in 2002. It was observed that the amyloid aggregation mechanism of higher forms of animals and yeast bear a lot of similarities. It was also observed that expanded polyQ repeat in the human Huntingtin gene has a similar cytotoxic effect on the Yeast cells also. It interfered with the cell cycle, slowed the cell growth and led to formation of nuclear and cytoplasmic protein aggregates. It was also studied in yeast that a protein called Yeast Metacaspase I (Yca1), is directly associated with the accumulation of 103Q repeats in the nucleus. Disruption of this gene prevented the nuclear accumulation of proteins and increased their growth rate. Disruption of endocytosis in presence of the mutant huntingtin protein suggests that these proteins are also having polyQ rich region. (Bocharova et al. 2009). As many of the pathways that are present in humans are conserved in Yeast, it has also been used in studying the Huntington’s Disease. In Yeast, the researchers have studied the impact of mutant Huntingtin protein using four types of mutant huntingtin genes. The poly-glutamine repeat number was altered in all four of them. The Four varieties are 25Q, 47Q, 72Q and 103Q. They were augmented to a GFP (Green Fluorescent Protein). This construct was ligated into a plasmid and using various transformation techniques like electroporation, chemical transformation, the plasmid with the construct was introduced into Yeast. This Huntingtin gene was put under a constitutive promoter, so that it is continuously expressed and there is no necessity to induction. The effects of various chemicals are also studied using these Yeast cells. The amyloids can be observed using Fluorescence microscopy and Fluorescence Assisted Cell Sorting (FACS). Effect of Huntington Disease on Energy Metabolism: It was also demonstrated by research that Huntington’s disease also had an adverse effect on energy metabolism. The ratio of phosphorcreatinine to the inorganic phosphate available declines in the HD patients compared to that of controls. The lactate-pyruvate ratio in the Cerebrospinal Fluid (CSF) showed significant increase. When the patients were treated with the co-enzyme Q10 , the lactate ratio increased and again declined as soon as the therapy was withdrawn.(Koroshetz et al. 1997)
Metabolic De-arrangement in Huntington’s Disease: A group of researchers took the brain tissue from a HD patient after the post-mortem and using LCMS and NMR, scanned the metabolic profile of the tissue. They compared it with that of the control cohort and the following results were obtained. They demonstrate that “concentration of metabolites like Uric acid, carnitine, 1-methyl adenosine, 1-methyl histidine, kynurenic acid, showed significant reduction”. The following is the table describing the metabolic profile of HD patient’s brain tissue from frontal region and striatum region, compared against the control cohort. The affected pathways are also shown. (Graham et al. 2016)
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