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Huntington’s Disease

Huntington's disease is a chronic genetically inherited disease. It is a degenerative disease with no current cure. Someone with the disease can, at best, only get palliative care. It is a movement disorder associated with defects in the nerve cell of the basal ganglia, an area of the brain, which is responsible for body movement and coordination. It prevails more in older people and onset is usually in middle age. It is characterised by chorea which is pronounced involuntary, irregular and jerky, movement. Muscles of the face neck and trunk are also affected. As the disease progresses patients often develop dementia, which is mental deterioration due to physical changes in the brain.9 But recent genetic discoveries have helped, greatly, explain its pathology and inspired exciting, unprecedented, ideas for new drugs and genetic therapies.

Genetics Behind The Disease

Huntington disease is autosomal dominant, meaning it’s a mutation on one of the non-sex chromosomes that is always expressed. The chance of passing the gene to offspring is 50% for each pregnancy.8 In affected individuals; one gene of the gene pair (that codes for the huntingtin protein) is not functioning correctly and dominates the other working gene. Since it is not on one of the sex chromosomes, it can affect both males and females. Males and females have the same chance of having the disease.

Family tree (4) Chromosome(4)

In recent years the gene for Huntington disease has been pin pointed to be on the fourth (4p16.3)10 chromosome of the forty six chromosomes found in humans.

The chromosome is composed of many genes, and each gene is composed of a string of molecules called nucleotides. The nucleotide bases are adenine (A), cytosine (C), guanine (G), and thymine (T). Each gene is made up of a series of three nucleotides which form the structure of DNA in the gene. Each gene has its own unique sequence of base pairs which is the code. The genes unique sequence codes for specific amino acids molecules, the building blocks of proteins.

Responsible - triplet repeat mutated Huntingtin Protein

In the HD gene, the DNA sequence, CAG (cytosine-adenine-guanine), is part of this sequence.8 This sequence may be duplicated many times in individuals, up to 29 times in a normal person. The duplication of this segment is a type of polymorph called trinucleotide repeat in which these three nucleotides (CAG pattern) are repeated over and over again to different extents in all persons. Individuals with 40 or more repeated CAG segments will definitely develop Huntington disease; this is a mutation, specifically a triplet repeat mutation. Specific laboratory and clinic evaluations are needed to interpret other repeat levels such as between 30-34, indicating those who will not develop the disease but transmit it for even generations before it develops into disease. And 35-39 who may not develop it but will definitely have it develop in their immediate children, greater than 55 will even have disease onset in childhood. It appears that people who have 29-35 repeats will not develop HD themselves, but a small percentage of their children may develop it. The disease also gets more pronounced from parent to child (with increasing mutant trinucleotide repeat polymorphism). This observation suggests that more CAG triplet repeat mutations occur during subdivision of DNA in newly formed sperm or egg cells.13 This phenomenon known as "genetic anticipation" since each time the polymorphic DNA is passed on to children, the children experience anearlier onset than their parents.16This is well supported by the fact that the extent of polymorphism statistically correlates to age of onset10 and this is a clear genetic link to the disease pathophysiology. Since the identification of the Huntington's disease gene in 1993, a number of ideas have been brought up that may improve treatment or even cure this disorder. Researchers are deciphering the lethal gene's structure in order to determine how its makeup plays a role in disease development.4

This discovery of the defective gene has also opened up an opportunity to diagnose the disease before onset of symptoms and a test was developed. A genetic test is now available from Regional Genetic Clinics throughout the UK19. But this is currently a blank development as it of no benefit to have that knowledge and it has been met with emotional resistance and ethical criticism; 8 however it will be most useful when a clinical cure is developed as the carrier will receive prophylactic treatment. The advantage of this is appreciated when the debilitating symptoms are considered and strides are being made towards this effect.

Role Of Mutant Huntingtin In Disease Pathophysiology

The polar zipper(7)

Studies into the genetics of the disease’s pathophysiology show the malfunctioning huntingtin protein produced has an altered "polar zipper"17 which is a fold within the huntingtin consisting of interactions between polar residues on separate subunits due to the elongated stretch of amino acids called glutamines, polyglutamines12 (coded for by the CAG base sequence). This conformational change alters how the protein interacts with other agents. One such agent is a brain-specific protein, HAP1, which binds extra tightly to the abnormal huntingtin.16 This genetic discovery may explain why nerve cells are affected as its strong binding leads to its accumulation in the nerve cell nuclei.16

  • Caspase Hyperactivation

How the defective huntingtin brings about the death of nerve cell is not specifically understood, largely because the function of normal huntingtin is not clearly known, but its role in development has been demonstrated.2 Current genetic studies are bringing possible disease pathways to light. Inside healthy nerve cells, enzymes called caspases are involved in the destruction of damaged cells. The process of cell death is called apoptosis. However, in a person with Huntington's disease, apoptosis goes out of control, and large areas of brain tissue are destroyed due to hyperactive caspases. There are different classes of caspases involved in apoptosis. Initiating caspases (IC) start the apoptosis in response to some external signal, whilst simultaneously activating the effecting caspases (EC). EC then cause nerve cell break down.1

Research has shown that this process is triggered by the abnormal expression of the huntingtin protein which accumulates and aggregates in the nerve cells. IC responds to the presence of the abnormal huntingtin protein in the nucleus by cutting it into smaller pieces. These smaller pieces of huntingtin activate EC, which in turn cut up more huntingtin, and a cascade of caspase activity results.

  • Mutant huntingtin Toxicity

The cut up huntingtin is easily aggregated in the cell nucleus, and the aggregates themselves are not proven to be toxic to the nerve cell but indirectly. Studies indicate that the aggregation of mutant huntingtin interferes with gene transcription of proteins essential for cell survivalespecially neurotransmitter receptor proteins15.Initiation of aggregation requires a critical concentration of the defective huntingtin is associated with a lag time, which may account for the late onset of the disease3

Primarily affected are spiny nerve cells of the basal ganglia that secrete gamma-aminobutyric acid (GABA), a neurotransmitter that controls the release of dopamine from other nerve cells. Selective loss of these specialized cells results in decreased inhibition of the thalamus, resulting in increased dopamine activity in certain regions of the brain's cerebral cortex lead to the disorganized, excessive, jerky, movement patterns.11

  • Interference with Metabolism

The abnormal huntingtin also binds to important glycolysis enzymes (GPD) via its polyglutamine stretch, inhibiting it, leading on to decreased mitochondrial function, which in turn leads on to decreased ATP production: the cell responds by increasing glycolysis to meet its energy needs. This increases lactate production which kills the nerve cells when it accumulates. Decreased ATP formation leads to failure of the Na+/K+ pump, membrane depolarisation leading to hyperactivation of the NMDA type glutamate receptor leading to an influx of Ca2+ and oxides that form free radicals. Oxidative cell damage that leads to cell death occurs which has a positive feedback on mitochondrial dysfunction.11

Overally the abnormal huntingtin affects several processes that lead to nerve cell death.

  • Identification of New Drug Targets

In this light of these discoveries there is new insight into the disease progression and identification of possible stages and sites for developing new drug targets like developing a drug that could target to prevent the binding of the abnormal huntingtin to HAP1 as this binding may contribute to the debilitating symptoms associated with the disease as this binding keeps huntingtin inside the nerve cells orprevent aggregation of the huntingtin as this may be toxic to nerve cells, pharmacological intervention aimed at inhibiting aggregate formation has recently shown beneficial effects in a mouse model of the disease.6

  • Development of NCE

Already scientists have already found a drug which appears to slow the disease progress. It was found that this drug rapamycin can reduce the levels of a mutated huntingtin protein. It does this by speeding up the breakdown of the protein in nerve cells. Animal tests by the Department of Medical Genetics at Cambridge

University researchers showed that this drug, rapamycin, also delays the onset of the disease. The drug is already used in humans to prevent organ rejection after transplants.5

As recently as within the last few years scientists have also found that a drug called (histone deacetylase) HDAC inhibitor appears to counteract the defective HD gene activity. The drug was initially tested in fruit flies with the HD gene. The flies raised on food containing HDAC inhibitors had reduced levels of brain cell damage and lived longer than HD flies that didn’t receive the drug. The test was also successful in mice, a more accurate representation of human physiology. The reduced brain cell damage and improved movement abilities. The inhibitor is so promising researchers are actually testing an HDAC inhibitor in about 60 patients with the disease.17

  • Gene Therapy Approach

Research is going even beyond the expressed faulty protein but actually as far as switching off the genes that code for them! This has been demonstrated by a groundbreaking study, in which scientists from the University of Iowa have shown for the first time that it is possible to stop a progressive brain disease in mice with a genetic technique known as RNA interference (RNAi) which works by targeting then shutting down or "silencing" a disease gene while leaving other healthy genes untouched.

RNAi treatment was given to mice with the disease and they did not develop the symptoms seen in untreated mice. The treated mice show any signs of suffering from toxic side-effects, indicating that the technique is safe!

The research brings to light the possibility of using genetics to effectively treat the disease. Due to the very unusually positive side-effect profile of this treatment it could be made available to patients in less than ten years. 18

Conventional gene therapy had not been successful as the disease is expressed by a dominant gene.18

Dying neuron CBP (14)

Similar work suggests that people with Huntington’s disease the faulty HD gene and the defective HD protein it produces interfere with processes that normally help cells survive in the brain. Studies found that the HD protein binds (cAMP-response element BindingProtein) CBP, which normally aids cell survival as it is a transcription factor. It was demonstrated that a nerve cell injected with genetic material that produces the defective HD protein began to die away, indicating that the presence of mutant huntingtin is associated with areduced transcription and expression of several important genes essential for cell survival. But when a variety of CBP, altered to resist the negative effects of huntingtin, is injected into the cell, the cell recovered. This development can be further manipulated in slowing down disease progress or even arrest its progress! 17/12

All these discoveries and advances in the genetic knowledge of Huntington’s diseases offer more in-depth understanding of its pathology and exciting developments that could lead to improved care in the future and help patients live a longer, healthier life.