IntroductionNeurodegenerative diseases are becoming increasingly important in today's world. Whether it is lifestyle changes or heredity… the number of cases in this area of ​​medicine is constantly increasing. The most common are Alzheimer's dementia and Huntington's chorea or Huntington's disease. While Alzheimer's disease is mostly associated with memory loss and loss of logical thinking, Huntington's disease has more physical and psychological implications together. The next session briefly discusses the causes and symptoms of Huntington's disease and some statistics. Say no to plagiarism. Get a tailor-made essay on "Why Violent Video Games Shouldn't Be Banned"? Get an Original Essay Statistics There are two possible possibilities of a person being affected by this disease. The majority of cases are due to inheritance, but a small fraction of cases are also attributed to a de novo mutation in the patient. As mentioned above, Huntington's disease is a late-onset disease. The following image describes the appearance of the disease in various age groups. Introduction to Huntington's Disease: Huntington's disease is a neurodegenerative disease caused by an autosomal dominant mutation that causes the destruction of a protein called Huntingtin protein. The mutated gene was passed down from generation to generation. It is a late-onset disease whose symptoms appear in Only 10% of all cases are due to a mutation in the same individual. This particular mutation causes the expansion of the polyglutamine[Q] repeat in the first exon of the Huntingtin protein. The exact purpose of the Huntingtin protein is not yet known; appears to have some vital activity in the nerve cells. The protein Huntingtin has been reported to interact with many proteins found only in the human brain. So the altered form of the protein is likely to have huge deleterious effects on the body's neurological function. With more glutamine repeats, the protein begins to aggregate and form a fibrillar structure that resembles the β-amyloid fibrils of Alzheimer's disease. Research has shown that it is not only the length of the poly-Q repeat that actually governs amyloid formation, but it also influences the concentration of amyloids at any given time. Yeast is often used as a model to study most amyloids. neurodegenerative disorders for the following reasons: · It has a very short generation time (80 minutes) and shares 50% similarity with humans at the genome level. It is relatively easy to handle yeast and grows quickly and the ideal temperature is around room temperature (30°C). C). Most critical pathways are conserved in yeast. It is the first organism whose genome has been completely sequenced. There are a total of 6000 genes and 5/6 of them have non-essential functions. They can exist in both diploid and haploid states. They also have a natural 2 µm plasmid, which can contain quite large genes. They possess several strong promoters that can easily increase the amount of expressed proteins. Yeast as a model for the study of neurodegenerative diseases: although yeast does not have a nervous system, all the pathways that form the basis of the nervous system and various diseases that affect the nervous system, such as mitochondrial and proteasomal dysfunction, transcriptional regulation , traffic problems. If an analogue of the gene that causes the human disease is present directly in yeast, the study becomes much simpler. Even if no analogue is available, it is very simple to study a given human gene usingheterologous expression in yeast cells. Diseases such as Alzheimer's also fall into the category of diseases caused by the misfolding of proteins. The amyloid hypothesis which refers to the formation of fibrillarly aggregated proteins due to aberrant protein interactions was actually formulated after rigorous studies on Alzheimer's disease. So it is clear that some of these serious neurodegenerative disorders are also caused by protein misfolding; mostly due to a mutation in the given protein. The next session refers to the role of yeast in the study of Alzheimer's disease. Role of yeast in the study of Alzheimer's disease: Alzheimer's disease or AD is one of the deadliest neurodegenerative diseases and is on the rise in today's society. Symptoms of this disease often vary but include characteristic dementia, cognitive dysfunction, and severe behavioral changes. In most cases there is no clear causative agent or gene, but an autosomal dominant mutation in the amyloid precursor protein (APP), presenilin-1 and 2 (PSEN-1/PSEN-) is observed in a fraction of affected individuals. 2 ). The characteristic feature of this disease is the presence of tangled fibrils within the neurons and amyloid plaques in the extracellular region. The main component of these plaques are Beta peptides, which are the result of the proteolytic cleavage of defective APP by the sequential action of β and γ secretases. 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 discover that the gene responsible for the expression of β and γ secretase is absent in yeast. Although their close relative exists in the form of aspartyl protease (α-secretase-like activity), it has not been as useful. The scientists then used the process of heterologous recombination and successfully demonstrated the expression of γ secretase by expressing its four components. Aβ42 aggregation has also been successfully studied in vivo by exploiting the SUP35 gene which encodes transcription termination and undergoes spontaneous changes and loses its function. The new yeast models also showed the involvement of HSR genes. (Miller-Fleming, Giorgini and Outeiro 2008) Role of yeast in the study of Parkinson's disease: Parkinson's disease is characterized by muscle rigidity, instability in posture and tremors at rest. Concentric cytoplasmic inclusions composed of hyaline, called Lewis bodies (LB), are identified by histological analysis. They contain the protein α-synuclein and some subunits of molecular chaperones. The currently proposed theory was that these LBs were developed by neurons as a protective mechanism against the accumulation of pathogenic intermediates. The disease has both familial inheritance and sporadic onset. The study of PD using yeast as a model began by cloning the wild type α-syn and the other with a mutation in 53 from AtoT (A53T). The formation of inclusion bodies was concentration dependent. Both wild type and mutant α-syn have been shown to target the plasma membrane and also cause stress on the endoplasmic reticulum. It also inhibited phospholipase-D and thus the function of endocytosis, which included the formation of lipid droplets, was impaired. (Ciechanover and Kwon 2015)Amyloids and their effects on cellular integrity: Various organisms have developed mechanisms to eliminate misfolded proteins from their systems very efficiently. Processes such as ubiquitination and sumoylation have improved their efficiency over the course of evolution. However, there are some cases where the degradation pathways ofproteins are rendered unusable. One such case is the formation of amyloid. It could happen as a result of various mutations. Misfolded proteins that are not eliminated by cellular machinery form insoluble aggregates called inclusion bodies (IBs). These disrupt the normal functioning of cells in many ways and cause a lot of damage. In most systems and organs, all old cells die and are replaced by new cells. The muscular and nervous systems are exempt from this phenomenon. The cells in these two systems are not replaced that often. If cells are recycled regularly, this protein aggregation may not have as many deleterious effects on the human body. If this happens in a neuronal cell, then it is of great concern, because they cannot be recycled and replenished. This is precisely why most amyloid-producing diseases are often neurodegenerative diseases. Although there is no clear evidence of the mechanism by which these amyloids cause neurotoxicity, some potential hypotheses have been proposed in recent years. Some say that amyloid formation stops ubiquitin-mediated protein degradation because proteasomes are stuck in the thick amyloid bundles. Amyloid formation has also been observed to affect several transcriptional processes, as transcription factors (32, 45, 46) have an abnormal affinity for IBs. (Meriin et al. 2003). Role of yeast in the study of Huntington's disease: Yeast is said to be one of the most useful models for the study of any amyloid aggregation disease, particularly Huntington's chorea. The first yeast-based model for studying Huntington's disease was presented in 2002. It was observed that the amyloid aggregation mechanism of higher forms of animals and yeast has many similarities. The expanded polyQ repeat in the human huntingtin gene was also observed to have a similar cytotoxic effect on yeast cells. It interfered with the cell cycle, slowed cell growth, and led to the formation of nuclear and cytoplasmic protein aggregates. It has also been studied in yeast that a protein called yeast metacaspase I (Yca1), is directly associated with the accumulation of 103Q repeats in the nucleus. Destruction of this gene prevented the nuclear accumulation of proteins and increased their growth rate. The disruption of endocytosis in the presence of the mutant Huntingtin protein suggests that these proteins also have a polyQ-rich region. (Bocharova et al. 2009). Because many of the pathways found in humans are conserved in yeast, it has also been used in the study of Huntington's disease. In Yeast, researchers studied the impact of the mutant Huntingtin protein using four types of mutant Huntingtin genes. The number of poly-glutamine repeats was altered in all four. The four varieties are 25Q, 47Q, 72Q and 103Q. They have been increased to a GFP (Green Fluorescent Protein). This construct was ligated into a plasmid and using various transformation techniques such as electroporation and chemical transformation, the plasmid with the construct was introduced into Yeast. This huntingtin gene has been placed under a constitutive promoter, so that it is expressed continuously and there is no need for induction. The effects of various chemicals are also studied using these yeast cells. Amyloids can be observed using fluorescence microscopy and fluorescence-assisted cell sorting (FACS). Effects of Huntington's disease on energy metabolism: research has also. 2016)