An extensive look at Huntington's disease
What is Huntington’s disease?
Huntington’s disease (HD) is an inherited genetic neuro-degenerative disorder. It is caused by a mutation in the Huntingtin gene which codes for a protein known as mutant Huntingtin (mHtt). The role of the normal Huntingtin protein is still not fully understood, although it is currently heavily researched by those that believe the cure to HD lies in the understanding of the normal protein. One interesting discovery about the Htt protein is that it is not isolated to the brain but it can be found throughout the body. The brain only has the highest concentration of the protein along with the testes.
The main parts of the brain that is affected by mHtt is the nerve cells of the basal ganglia, a brain structure the base of the hypothalamus which is involved in the organisation and control of muscle based movement. The protein, mHtt, aggregates in the cells and disrupts normal cell function, causing a decline in motor and cognitive function and also various behavioural symptoms.
Symptoms, which can include decline in mood and cognition and the recognisable uncontrollable jerky body movements, will vary from person to person and can also vary within the same family. These symptoms does tends to follow a predictable path of progression from which life expectancy can be deduced. Normally HD patients have a life expectancy of around 20 years after symptoms appear, which normally starts between the ages of 35 and 44 but can start anywhere from infancy to old age.
A person with Huntington's disease talking about his experience.
A look at the history of Huntington’s disease?
Huntington’s disease has been a known condition since the Middle ages although it had many names based on what was known about the disease. The first full description of HD only came in 1872 when George Huntington wrote the paper "on Chorea" after examining the full medical history of multiple generations of the same family. Huntington writes the following in his paper “There is no loss of sense or of volition attending these contractions, as there is in epilepsy; the will is there, but its power to perform is deficient, the desired movements are after a manner performed, but there seems to exist some hidden power, something that is playing tricks, as it were, upon the will, and in a measure thwarting and perverting its designs; and after the will has ceased to exert its power in any given direction, taking things into its own hands, and keeping the poor victim in a continual jigger as long as he remains awake, generally, though not always, granting a respite during sleep.” What is described here is how people with HD do not completely lose the ability to control their movements and unlike epilepsy sufferers, who tend to be unaware of their bodies during attacks, HD sufferers are fully aware of their movements.
Huntington was also the first to discuss the hereditary nature of the disease stating in his paper “Of its hereditary nature. When either or both the parents have shown manifestations of the disease, and more especially when these manifestations have been of a serious nature, one or more of the offspring almost invariably suffer from the disease, if they live to adult age. But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.” His paper can be found on https://en.wikisource.org/wiki/On_Chorea.
The hunt for the cause of the disease started in 1968 when the Hereditary Disease Foundation (HDF) was started. In 1979 the HDF held a workshop and participants suggested mapping the human genome to find a marker for HD. The HDF and the National Institute of Neurological Disorders and Stroke (NINDS) organised the US–Venezuela Huntington's Disease Collaborative Research Project. The project studied one of the world’s largest families living with the disease. In a rural fishing village in Venezuela. The founder of the family lived in the 1800’s and in 1979 the extended family encompasses over 18,000 individuals spanning 10 generations. More than 14,000 of them living at that time, most of which where already affected by HD or at risk of developing HD.
In 1983 the location of the HD gene was discovered using recombinant DNA technology which at the time was a new technology. The discovery demonstrated that the new technology could be used to locate other disease genes. The precise HD gene was isolated in 1993, it was one of the first disease genes to be fully isolated.
An in-depth look at the genetics involved in Huntington’s disease.
Function of the Huntingtin protein.
Functions of Htt that has been found include; intracellular transport, inhibition of programmed cell death, regulation of transcription and embryonic development.
Using fluorescent techniques Htt has been tracked through the cell and shown to be involved in intracellular transport, the movement of molecules and organelles inside the cell.
Cells regularly undergo programmed cell death, when a cell destroys itself due to being defective or old. In nerve cells, that doesn't readily undergo mitosis and multiply, cells dying can result in a lack of nerve cells causing neurodegeneration. When Htt is genetically knocked out in mice it results in massive nerve cell death, showing that Htt inhibits programed cell death.
Htt interacts with a molecule that normally repress the transcription, a process by which DNA is turned into mRNA, of a specific gene. When Htt binds to the molecule it can't enter the nucleus and isn’t able to repress the gene. The gene in question codes for a protein known as brain-derived neurotrophic factor (BDNF) which is responsible for the growth and survival of certain nerve cells. When there is no Htt or when mHtt is present in high quantities there is nothing that binds to the molecule which is then able to bind to the gene and stop the production of the protein.
Experiments in mice has shown that Htt is needed for embryonic development, a foetus will on average not survive more than 8 days when Htt is knocked out in mice.
It is mHtt toxicity that has the primary effect on the cells and not the lower levels of Htt which is only a secondary effect. This was shown by experiments attempting to add more Htt to the diseased cells, it showed some improvement but was deemed to be unable to cure HD.
The wide range of functions and interactions, Htt interacts with over a 100 other proteins, of Htt is why it is so difficult to cure/treat HD.
Structure of Htt
The Htt gene has a sequence of CAG (cytosine-adenine-guanine) repeated a certain number of times. This is known as a trinucleotide repeat. CAG is the codon for glutamine as all proteins has a single letter code for easy reference, for glutamine it is Q, this region is also known as the polyQ region. The degree of HD depends on the number of repeats in this region. The test for HD also depends on theses repeats and works by detecting how much repeats there is in the gene and then from that it can be determined if and how severe the disease will be.
In the image above it can be seen how these repeats are translated into risk of getting Hd. People with 26-35 CAG repeats will not develop HD but due to the instability of the region and random mutation that can occur there is a change of that person passing on a gene with more repeats. The number of repeats is only about 60% of what determines the age of onset the other 40% is due too environmental factors and other genetics.