Introduction
Huntington’s disease is a neurodegenerative disorder that is inherited in an autosomal dominant fashion. The cytoplasmic protein affected in Huntington’s disease is Huntingtin, coded for by the Huntingtin gene. The mutated version of the Huntingtin protein has several degenerative consequences on the molecular level. These are mainly caused by the elongated chain of glutamines that abberantly interacts with proteins and diminishes their biological functions. The mutated protein also tends to misfold and form aggregates in neurons, diminishing normal neural functions and producing the phenotypic traits characterized by Huntington’s disease.
Discovery & cause of the mutated gene The symptomotology of Huntington’s have been recognized for several hundreds of years, but the etiology was ambiguous until recently when it was discovered that an expansion in the polyglutamine tract led to misfolding (citation). Although a lot of progress has been made, the way in which the mutant Huntingtin protein damages cells is still not fully understood. The events that preceede the discovery were crucial and are a perfect example of the use of pedigrees and linkage analysis to identify the locus of the causal gene of a disease. The first step in identifying the Huntingtin gene was to use pedigrees of affected families to establish that Huntington’s disease as an autosomal dominant inheritance pattern [79]. Over 100 scientists were involved in the following 10 year Huntington’s
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.
Huntingtin is a 350-kilodalton protein of unknown function that is mutated in Huntington's disease (HD), a neurodegenerative disorder. The mutant protein is presumed to acquire a toxic gain of function that is detrimental to striatal neurons in the brain. However, loss of a beneficial activity of wild-type huntingtin may also cause the death of striatal neurons. Here we demonstrate that wild-type huntingtin up-regulates transcription of brain-derived neurotrophic factor (BDNF), a pro-survival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. We show that this beneficial activity of huntingtin is lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This
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.
One disease that can be tested for using these methods is Huntington’s disease, which causes involuntary spasms and contractions and a decline of coordination and cognitive ability (Online Mendelian Inheritance in Man [OMIM], 2014). These symptoms occur as a result of a trinucleotide repeat in the huntingtin gene on chromosome 4p16.3, also known as the HTT gene. The disease is autosomal dominant, with the completeness of its
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 is a genetic autosomal disorder which effects the brain. It affects about 1 in 20,000 individuals. The symptoms of the disease do not start to occur until after or around 40 years of age. With the onset of the disease the patient starts to gradually deteriorate intellectually, this deterioration also causes involuntary movements. Scientists have only recently found the section of the gene which causes Huntington's disease, and this is allowed them to devise pre-symptomatic tests. However, a cure for the disease is yet to be found.
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
At present, there is no cure for the disease, but dynamic progress has been made as researchers explore this illness. HD is inherited as an autosomal dominant condition. In March 1993, scientists realized that HD is caused by a mutation in a gene located on chromosome 4. This gene has a unique genetic sequence for CAG (cytosine-adenine-guanine) and codes for the amino acid glutamine, a building block for the huntingtin pr otein. Normal individuals have this sequence duplicated from 11 to 40 times in their genetic coding without having symptoms of HD. However, individuals with the disease have from 40 up to 100 repeated CAG segments. Juvenile Huntington's Disease occurs wit h 60 or more repeats, linking the longer chains of CAG sequences to earlier and more aggressive onset of the disease.
Huntington's disease is an autosomal dominant disorder, which is found on the # 4 chromosome. George Huntington discovered it in 1872. It mainly has an effect on the nervous system. There are around 210,000 bases between D4S180 and D4S127. The disease itself is found in 2% of people in their childhood, and in 5% of the people they were older then 60. (Miller p 16) In the majority of the affected people the disease is detected between the ages of 35-45. In males the disease begins around the time of their childhood. However, in females it begins later in life. This severe symptom has a tendency for the condition to worsen as it is passed on from generation to generation. Huntington’s disease is paternally
() The premier levels of this protein are found in the Central Nervous System neurons and the testes. (pro) These proteins are also located in smaller amounts in the liver, lungs, and heart. Localization studies show that the protein appears in the nucleus, endoplasmic reticulum, mitochondria, and Golgi complex. (EJN) This protein has a very distinct portion called the polyQ stretch. (Cattaneo 2005 ) A polyQ stretch is made up of 34 or more glutamine residues. (Cattaneo 2005) This region is found in many transcriptional factors and other disease causing proteins. (Cattaneo 2005) The exact function of this protein is not known, but there is information known stating that it is necessary to have them in early development and nerve cell stability. (Cattaneo 2005) A study was done to show what happens to a mouse embryo by completely disabling the normal Huntington protein. The results of the disruption caused the embryo to die on day 8.5. This occurred before gastrulation and the development of the nervous system. (Cattaneo 2005) This supports the fact that a normal Huntington protein aids in the early stages of development. After the gastrulation process, the Huntington protein becomes necessary for neuron stability. The study for this had less than fifty percent of the wild type Huntington protein in the mice. This revealed a weakness in the neural structure called epiblast. (Cattaneo 2005) The
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
Huntington’s disease is a neurodegenerative disease that is procured from a repeat expansion of CAG in chromosome 4 the Huntington’s gene. “When the number of CAG repeats passes 39 then the disease will inexorably occur at some point in life” (Cepeda). Scientists currently do not know for certain why the cells within the basal ganglia specifically die in Huntington’s patients because the huntingtin protein is present is all cells not just exclusively nerve cells. The normal function of the huntingtin protein is relatively unknown but it is necessary for growth and development and is active throughout the body. “The huntingtin protein undergoes a posttranslational modification, and some events like phosphorylation play a large role in helping
In 1983 the Huntington disease gene, discovered as 4p, was the first to be mapped to a human chromosome without any prior indication of the gene location; furthermore, ten years later with the pathogenic mutation identified as a CAG-repeat, an ongoing debate for predictive testing of the disease is
at the University of Pittsburgh department of Neurological surgery, I held a position on a research team that dealt with the neuropathological mechanisms of Huntington's disease (HD). The focus of my assigned project was to demonstrate a defect in mitochondrial protein import in those cells that expressed the mutant huntingtin protein. The majority of mitochondrial proteins are encoded in the nucleus, translated on cytoplasmic ribosomes, and exported to the mitochondria in premature form carrying a mitochondrial targeting sequence on N-terminal side of protein. These proteins are transported through the mitochondrial subunits TOM (translocase of outer membrane) and TIM (translocase of inner membrane). The data demonstrate that mutant huntingtin fragments directly interact with the TIM subunits and inhibits protein transport into the mitochondria. Based off of these findings it was hypothesized that due to this interaction between mutant HTT and TIM, the level of mitochondrially-targeted proteins will be reduced in mitochondria. My specific role in this project was to execute a comparative proteomic strategy consisting of protein separation, identification, and validation. Separation was performed by 2 Dimensional Gel Electrophoresis (DIGE) and identification by liquid chromatography followed by mass spectrometry
A) Huntington’s Disease has been the focus of various research experiments for many years. Thanks to the consistent research that has been done in this field, we have come to learn many things about