Huntington's Disease, An Overview

By Jason Luo

It is no doubt that neurological disorders and conditions are extremely lethal as they can attack one of the most vital organs in the body: the brain. Our brains are responsible for our daily functions such as regulating coordination, encoding information, and storing short/long term memory through our neurons and brain cells. Huntington's disease is a genetic and neurological disease that causes the death of nerve cells in the brain. This article will look at the effects and symptoms of Huntington's disease as well as how it is diagnosed and treated in affected patients.

Huntington’s disease is an autosomal dominant brain disease that results from an expanded mutation in the HTT gene on chromosome 4. The wild-type HTT gene is responsible for synthesizing a protein called huntingtin that plays a role in chemical signaling, transportation of materials, and the prevention of apoptosis. Huntingtin, while present all over the body, is most abundant in the brain and is related to the proper function of nerve and brain cells. The mutation in the HTT gene causes a DNA segment in the gene called the CAG (cytosine, adenine, guanine) trinucleotide to appear more than normal. Normally, the HTT gene has 10-35 CAG trinucleotides but the resulting mutation results in the CAG trinucleotide appearing 36-120 times. Typically Huntington's disease develops in patients between the ages 30-50 but can develop from as early as 2 years old to as late as 80 years old.

The mutant HTT gene causes the synthesis of an abnormally long huntingtin protein that contains increased numbers of polyglutamate (polyQ) tracts on exon 1. The increased amounts of polyQ tracts have been shown to lead excessive amounts of the neurotransmitter glutamate, which acts as an excitotoxin, causing excessive firing and activation of the neurons and is supposedly responsible for the symptoms in Huntington’s although the specifics of this are not fully understood yet. Many studies performed on rats show that excessive amounts of glutamate have caused them to exhibit symptoms of Huntington’s.

Research done on mutant huntingtin has shown that it can cause various disruptions in gene expression that are necessary for a nerve cell's survival. For instance, mutant huntingtin has been shown to decrease the expression of GLT-1, a glutamate transporter which when expressed in normal amounts is responsible for uptaking and clearing the amount of glutamate in the synapse. Without GLT-1, glutamate will accumulate in the synapse without any way to remove it. This accumulation can be damaging as extremely high concentrations of glutamate means that the postsynaptic neurons will almost always have at least one glutamate ligand bound to its receptor. This can cause the neurons to become overexcited and fire absurdly, eventually leading to cell death. The mutant huntingtin has also been shown to cause an imbalance in the amount of synaptic and extrasynaptic NMDA receptors (NMDAR), which allow the binding of glutamate as a ligand in order to trigger cellular responses. Synaptic NMDAR is a pro-survival receptor that activates survival genes in the neuron when glutamate binds to it. In contrast, extrasynaptic NMDAR is a receptor that inhibits gene expression and instead induces apoptosis when glutamate binds with it. As a result, the increased amounts of glutamate and overexpression of extrasynaptic NMDAR results in accelerated nerve cell death.

Image Credit: Wikimedia Commons @ National Institute of Standards and Technology

The resulting loss of neurons can cause a wide range of symptoms. This can include developing movement disorders ranging from being as mild as minor speech impediments to more severe disorders such as chorea: the unpredictable and irregular movement of certain body parts like the arms and legs. Death in the nerve cells has also led to many cognitive disorders such as lack of awareness, difficulty focusing on certain tasks/learning new information, and random outbursts of anger and control of emotion. Patients with Huntington's have also shown signs of sadness, depression, and even suicide due to the sudden changes in the brain. The area in the brain where the most nerve cell death occurs is in the basal ganglia, which is responsible for regulating both motor movements and emotions and explains why most of the symptoms that occur are kinesiological or cognitive.

Huntington's shows a wide range of symptoms so there are many ways to diagnose a person who may be suspected of having the disease. A neurologist may interview the patient and ask them about any previous symptoms as well as their medical history. They can then perform various neurological and physical tests such as reflex, movement, hearing, and walking tests to evaluate certain motor and neurological functions and find any abnormalities in them. Genetic tests may also be used since Huntington's is a heritable disease and has an equal chance of affecting men and women. Blood samples may be taken from the patient and then be examined to determine the number of CAG repeats in a person’s HTT gene. Finally, brain imaging may be used to examine the shape and condition of a patient's brain. Computed tomography (CT) or magnetic renaissance imaging (MRI) are usually used as they give the most accurate picture of what a patient’s brain looks like. Those with Huntington’s can expect to see shrinkages in areas of the brain such as the striatum of the basal ganglia, but these results do not fully conclude a patient has Huntington’s as these symptoms show in other disorders as well.

Image Credit: Wikimedia Commons @ Frank Gaillard

Right now, there is no definitive cure for Huntington’s disease, and the treatment options available now only lessen the existing symptoms. Such options include using drugs such as Xenazine and Klonopin to suppress the jerky and sudden movements caused by chorea. While these drugs sound promising, they do come with their fair share of side effects such as worsening the existing symptoms of Huntington's like depression. Antipsychotic and antidepressants are also another form of treatment but they too can cause side effects such as dry mouth and can even worsen muscle rigidity and impair movement. On a brighter note, speech therapy, psychotherapy, and physical therapy can help cope with the most common symptoms of Huntington’s such as trouble swallowing/speaking, thoughts of suicide, and trouble walking. In addition, research being done on Huntington’s revolves around blocking the activity of NMDAR with NMDAR antagonists drugs like memantine. In the lab, scientists were able to use low doses of memantine in mice with Huntington like symptoms and it has been shown to reduce downstream cell death and improve the motor movement of the mice. Gene therapy is also being researched, particularly antisense oligonucleotide therapy. This type of treatment involves synthetic DNA and RNA strands called antisense oligonucleotides that bind to the mutant HTT gene, acting as a repressor similar to how microRNA regulates the expression of post-transcriptional mRNA. The binding would hinder the ability of the gene to synthesize the toxic protein and thus limit the symptoms of the disease.

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