Huntingtin Synthesis

Huntington’s Disease is a brain disorder affecting movement, cognition, and emotions (Schoenstadt). It is a genetic disorder generally affecting people in their middle 30s and 40s (Sheth). Worldwide, Huntington’s disease (affects between 3-7 per 100,000 people of European ancestry (Schoenstadt). In the United States alone, 1 in every 30,000 people has Huntington’s disease (Genetic Learning Center). Huntington’s Disease is a multi-faceted disease, with a complex inheritance pattern and a wide range of symptoms. There is also much research being done in the field of Huntington’s disease, because as of 2012, this disease is untreatable. THESIS.

Huntington's disease is an inherited neurodegenerative disorder. It is passed on to children from one or both parents (though two parents with Huntington's is extraordinarily rare) in an autosomal dominant manner. This is different from autosomal recessive disorder, which requires two altered genes (one from each parent) to inherit the disorder.

The genetic disorder is caused by a mutation in the DNA segment CAG found in chromosome 4 which results nerve cell death. Phenotypic characteristics include gradual motor dysfunction, psychological issues that correlate to degeneration of metal health, and cognitive degeneration. Studies on transgenic mice have allowed a better understanding of the proteins that relate to Huntington’s

Huntington’s disease destroys the organs that carry the functions of the central nervous system. Kalat (2013) states, “Huntington disease (also known as Huntington disease or Huntington’s Chorea) is a severe neurological disorder that strikes about 1 person in 10,000 in the United States” (A.B. Young, 1995, p. 258).Individual’s develop the symptoms in their middle age, but even if it is a rare disorders juveniles as well as children before the age of ten can develop the disease. Huntington’s disease is hereditary disease that is passed on from a parent. Huntington’s disease is of the lack of the chromosome 4, if one of the parents carries the gene, they can pass that gene to their

Huntington's Disease (HD) is an autosomal dominant, progressive, neurodegenerative disorder (Walker, 2007 and Harmon, 2007). The gene that causes the disease is located on the fourth chromosome and causes an abnormal number of repeats in the patient's genetic code (Harmon, 2007). Huntington's Disease can have devastating effects on patients' quality of life. The first symptoms of HD generally start between the ages of 30 and 45 and patients are typically asymptomatic prior to this time (Terrenoire, 1992 and Walker, 2007). However, the disease progresses with subtle changes in motor control, personality, and cognition. Patients eventually develop distinct

According to aggregation kinetics, the rate of aggregation formation is dependent upon the amount of polyglutamine polypeptides. Aggregates in Huntington’s disease are formed from the mutant huntingtin fragments when the protein is cleaved at the N-terminal. This occurs after a conformation change into a β-sheet conformation. Huntingtin is cleaved by caspase, known for apoptosis, and calpain. Cleavage at caspase-3 sites and inhibited cleavage caspase-6 sites did not produce Huntington’s disease characteristics. Mutant huntingtin proteins contain more active calpains because of the increase in neurotransmitter – glutamate – release, enhancing NMDA-receptor activity. An increased glutamate level on spiny neurons was found to increase apoptosis in nerve cells. There are currently no treatment or cures for Huntington’s disease. However, new therapy ideas are centered on the inhibition of proteolytic cleavage.

Neurodegenerative diseases continue to affect the lives of millions Americans each year, with incidence and prevalence rates ever increasing. These diseases cause degeneration or death of nerve cells in the brain. These diseases can cause a financial and emotional burden on not only patients themselves, but also family members and care givers as well. Molecular mechanisms that underlie these diseases have remained relatively unclear, despite much research. Understanding the mechanisms of these diseases are facilitated by utilizing model organisms to study pathways involved in neurodegenerative diseases. One such model organism is the Caenorhabditis elegans nematode. The C. elegans roundworm has displayed usefulness as a template to study neurodegenerative diseases in humans, including Parkinson’s disease and Alzheimer’s disease.

HD, in contrast, is not a condition offset by the environment, as PD is thought to be. It is indeed a condition due to cell death in the brain (basal ganglia) but is caused by an abnormal gene that codes for a mutant protein called huntingtin. Huntingtin, thus, interferes with normal brain cell functions by causing a depletion in neural cellular energy and neural death (12)(9).

Since the early 1900’s scientists and doctors have been scrambling to obtain the knowledge of how to cure and prevent degenerative diseases. Since these illnesses are currently the fifth-highest cause of death in the United States (State of Aging and Health in America, 2016), it has become imperative to find a cure. However, there are many

Parkinson’s disease, Huntington's disease, and Alzheimer’s disease are neurodegenerative disorders that share similar pathological features, including delayed onset, specific neurological damage, and protein dysfunction [1]. Over the past decade, the increasing prevalence of these disorders is apparent. Although the advanced research into these pathogeneses has identified related genetic mutations, the progression to which they link is too slow to reveal the underlying mechanism and correspondent treatment [2]. Today, the emergence of induced pluripotent stem cell (iPSC) technology has made a breakthrough in the recent neurological research and overcome the hurdles met by cellular and animal models.

The purpose of this lab is to extract trimyristin, a pure organic compound, from nutmeg, a natural substance. It is known that trimyristin accounts for between 20-25% of the composition of nutmeg. This procedure will teach us how to use solvents and heat to break down specific bonds so that we can extract a specific compound from a more complex molecule.

The exact answer to this question has yet to be discovered, but steps to explain why it affects the brain have been made. The Huntingtin protein (HTT) is known to be a necessary protein for development and is found throughout the whole body. However, it only kills the selective nerve cells; this suggest that the HTT protein only interacts with proteins associated with the brain. Various experiments revealed that HTT protein interacts with two other proteins (HIP-1 and HAP-1) which are both only present in the brain. This could explain how the HTT only affects the

Pro-opiomelanocortin (POMC) is a precursor polypeptide and is synthesized from the polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a signal-peptide sequence during translation. A cultivator of several hormones, POMC is synthesized in the pituitary gland. After separation by enzymes at various points, it can produce Beta-Endorphin (a neuropeptide produced by the hypothalamus and pituitary glands, and a neurotransmitter that is released when the body experiences stress or pain), and Adrenocoticotropic Hormone (ACTH).

I chose this article because it characterizes the transduction profiles of a variety of AAV vectors that cross the blood brain barrier and transduce cells throughout the CNS. I am particularly interested in this gene delivery strategy – especially as it may apply to clinical therapeutics for Huntington’s disease (HD), a genetic neurological disease that causes widespread degeneration throughout the CNS. I spent the last few years working on studies that characterized the transduction profile of AAV9 in the CNS and periphery in a mouse model of HD. The aims of these studies were to: 1) Assess whether or not AAV9 has a tropism for the specific peripheral tissues and CNS regions that are affected in HD; 2) Evaluate whether systemic delivery using an AAV9 vector would be suitable delivery strategy to deliver an RNAi construct that could reduce HD symptoms. Accordingly, by choosing this paper, I was hoping to build a better understanding of other AAV vectors (in addition to AAV9) that cross the blood brain barrier and potentially could be used for vascular delivery of an RNAi construct throughout the CNS.

Currently, there is no cure for Huntington’s disease (HD) and only limited numbers of treatments are effective in controlling HD symptoms. HD a progressive neurodegenerative disorder characterized by motor disturbances, psychiatric dysfunctions, and cognitive disabilities. HD is inherited in an autosomal dominant manner, means that the inheritance of a single copy of the mutant huntingtin allele containing an expanded CAG repeat region in exon 1 (>36 CAG repeat) causes the disease. Translation of the mutant allele mRNA yields the mutant huntingtin protein (mHtt) containing an expanded polyglutamine region near the amino terminus, which favor protein cleavage and accumulation of the N-terminus in the nucleus. N-terminal huntingtin affects transcription of subsets of genes. Early in HD progression, levels of the cannabinoid receptor type 1 (CB1) and dopamine receptor type 2 (D2) are reduced in the medium spiny neurons of the striatum. CB1 receptor is able to activate several signaling pathways through the activation of different G proteins as well as arrestin-2. Furthermore, compelling anatomical and physiological evidence suggests a strong interaction between the CB1 and D2 receptors. Given this interaction between CB1 and D2 receptors, drugs that block or activate either receptor will influence convergent signaling pathways. Typical and atypical antipsychotics, including haloperidol and olanzapine, respectively, are commonly prescribed to HD patients to control chorea and