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The Science of Huntington’s Disease

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Huntington’s Disease is a genetic disorder caused by an inability to produce properly formed Huntingtin Protein. The day’s functional protein is caused by a series of CAG repeats along one part of Chromosome 4. The altered Huntingtin causes neurological breakdown in the Basal Ganglia and cortex leading to difficult cross-brain communication and motor control dysfunction. The main risk of Huntington’s is that it is a disorder caused by a faulty allele that proves to be dominant over a healthy allele. This means that even if a person has one Huntington’s allele, they will prove to develop the disorder. This also means that if a person has Huntington’s, at least one of their parents will also have the disorder, unless it is a mutation, which then translate up the genealogy, putting many family members at risk.

Huntington’s Disease comes in several stages with each stage having a series of symptoms associated with it. The Early Stage starts minor with changes in coordination, difficulty with problem solving, small involuntary movements (Chorea), and mood changes such as irritability and/or depression. The Middle Stage comes with increases in chorea, decreased motor control, sometimes causing difficulty with speaking and swallowing, and changes in reasoning capabilities. The Late Stage shows symptoms including a complete loss of motor control, with worsening risks of speaking and swallowing complications, further loss of mental capabilities, and a complete dependency on others for aid and assistance. There are no cures for Huntington’s Disease but there are treatment options aimed at fighting some of the symptoms. Physical Therapy has shown some success in delaying motor control loss. Medication is available that is able to stop the chorea. Finally, as symptoms get worse, there are caretakers who are able to take care of the affected person as needed. An important concern is that weight loss is also associated with the disease which can be severely problematic and cause further complications.

Many People have compared Huntington’s Disease as to having Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis (ALS) all at once. This comparison comes from the combination of symptoms found with Huntington’s Disease affecting both motor control and mental capabilities. The mental degeneration of Alzheimer’s is very akin to the degeneration associated with Huntington’s disease though Alzheimer’s proves to be more severe. The chorea is a symptom found in Parkinson’s in addition to Huntington’s. Finally, the loss of motor control in Huntington’s is similar to the loss associated with ALS.

Huntington’s disease does its damage by killing striata like neurons, also known as Medium Spiny Neurons (MSNs). MSNs are utilized by the nervous system as a production center for Gamma Amino-Butyric Acid (GABA) as well as a transmitter within the brain. MSNs compose the majority of neurons found in the Basal Ganglia, particularly in the striatum. The Basal Ganglia is comprised of several types of neurons, though most are MSNs, and is associated with the transition of information between the cerebral cortex, thalamus, and brain stem and is involved in motor control, learning, and emotions. The Striatum is part of the Basal Ganglia that is responsible for the brain’s reward system through the control of Dopamine levels throughout the brain. 95% of the striatum is comprised of MSNs causing a dependence on MSN health to function. Gamma Amino-Butyric Acid (GABA) is a chemical, produced by MSN, that is used by neurons as an inhibitor, stopping communication between neurons. The nervous system uses GABA as a controlling method, to limit the firing of neurons. GABA binds to the synaptic neuronal processes and is used to regulate the flow of chloride and potassium ions across the cell membrane. This control controls the rate of fire for the neuron. This limitation causes the neurons to only fire when instructed to do so by another neuron, instead of randomly as the charge within the cell varies. The limitation by the GABA is used to fine tune the charge needed to cause the neuron to fire, allowing it to not be sporadic.

In a Huntington’s victim, the incorrectly shaped Huntingtin protein causes the MSDs to I’m die, causing a decrease in GABA production and broken connections across the brain. This breakdown of communication leads to the mental symptoms of the disease and the loss of GABA allows neurons to fire more randomly throughout the body, causing the physical symptoms. The effect of the loss of MSDs is substantial and is the result of the disease but because of the symptoms.

The exact reason that cells die when they have the incorrect Huntingtin Protein but there is speculation that it has to do with mitochondrial membranes within the cell. The mitochondria are critical for apoptosis, programmed cell death, within a cell. The mitochondria contain second mitochondria-derived activator of caspases, or SMACs, that, when released, bind to inhibitors of apoptosis proteins (IAPs) and deactivates them. With the IAPs deactivated, the apoptosis process begins and the cell will die. There is research to suggest that a dysfunctional huntingtin protein leads to weakening of mitochondrial membranes in MSDs, beginning the process of apoptosis.

There is another theory that the dying neurons will begin to release glutamate, the main neurotransmitter of the nervous system. This causes overstimulation of the living neurons leading to the release of calcium ions within the cell. The calcium ions can cause several damaging processes within the cell. The calcium may cause apoptosis as it can degrade the mitochondrial membrane, releasing SMACs and causing apoptosis. It can also cause the mitochondria to swell and potentially release other, weaker apoptosis causing chemicals or stopping respiration, also killing the cell. It is also important to note that sometimes the weakened mitochondrial membrane caused by the Huntingtin protein can release calcium into a cell, further weakening the membrane until SMACs are released. Calcium is another major cause of the symptoms of Huntington’s disease.

Huntington’s Disease is being studied in several ways. There is lots of research into the idea of silencing the dominant allele, allowing the normal recessive allele to be used in the production of normal Huntingtin Protein. There is also attempts to slow cell death through stopping the protein or through strengthening the cell against the effects of the misshapen protein. In addition, there has been the proposal to replace dead neurons through stem cell development. All of these treatments have had repeatedly proven to be ineffective or otherwise dangerous but a newer method of treatment may prove more valuable, CRISPR/Cas. The technology is founded around a natural antiviral technique found in E. Coli bacteria. When a virus implants its own genes into the cell, a strand of RNA finds these genes and bonds to them. Attached to the RNA is a protein that cuts out the viral gene and may replace it with the correct sequence. The viral gene is then ejected out of the cell and the cell remains uninflected. This idea has been applied to the idea of curing genetic diseases. An RNA strand matching the CAG chains could find, and attach to, the dysfunctional section. The attached protein would then cut out the bad chain and replace it with a healthy gene into the place of the cut. This would cause the cell to then produce normal Huntingtin protein, curing the disease. The method is being tested for many genetic disorders but there has been issues with people questioning the ethics of potential “designer babies” as well as the potential to accidentally replace normal genes, leading to another disorder. It is a risky potential but it also appears to be the most successful cure thus far and science will continue to try to find a cure.

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