Cells in our body (except sperm cells and eggs) have two copies of every gene, one copy from your father, and the other from your mother. Genes are like blueprints or instruction manuals that tell the cell how to make proteins, the building blocks of the cell. Thus, genes and the proteins they encode for determine everything about the cell: how it grows, what it looks like, how it will respond to signals from its environment. Changes, or mutations, to these genes will cause changes to the proteins and affect the cell, much like a word-change in a sentence will change its meaning.
In Huntington’s Disease, a repetition of a CAG sequence in the gene encoding for the protein Huntingtin makes it clump together in our brain cells, ultimately making the brain cell die. For each CAG sequence in the genetic blueprint, the cell incorporates, one after another, an extra glutamate, a building block of protein, into Huntingtin. Longer repeats of the CAG sequence mean more glutamates are incorporated into the protein. It’s like a blueprint of a house that normally instructs an architect to build a chimney on the roof. One chimney is fine, but if the blueprint has an error and tells the architect to build 40 chimneys on the roof, the house would likely collapse, ruining not just the house, but damaging the area around it. Houses built with 50 or more chimneys would be even more unstable and cause more damage. Chimneys, and glutamate, aren’t inherently harmful, it’s their improper incorporation into houses and cells, respectively. In brain cells, the more glutamates in Huntingtin, the more protein clumps form, more severe the damage, and the lower the age of onset. This explains the variable age of onset of the disease, or the age at which symptoms arise; different people have different amounts of the CAG repeat.
The mechanism of the disease is still being researched, but here’s what we do know. The repetitive glutamates in the Huntington protein change the shape of the brain cells, affecting their function. The glutamate sends signals that constantly over-excite brain cells. Their overexcitement leads to cell damage, and ultimately cell death. Changes in the breakdown of nutrients will lead to the production of toxic chemicals known as free radicals. The regions of the brain that regulate movement, impulsivity, and learning are most affected in Huntington’s Disease. As a result of brain cell damage and death, Huntington’s have trouble controlling their movement, with rigid joints, difficulty chewing and swallowing, involuntary tics and writhing movements called chorea. Cognitive manifestations include impulsiveness, lack of empathy, memory loss, ultimately leading to dementia. These symptoms become progressively worse as time goes on.
The disease is dominantly inherited. Only one bad copy of the gene from either the mother or father will result in Huntington’s Disease. Children of people affected with the disease have a 50% chance of getting it from an affected parent, irrespective of whether the other parent has a normal copy of the gene. If both parents have Huntington’s Disease, offspring have a 75% change of being affected by the disease.
Source: Annu. Rev. Neurosci. 2007. 30:575-621
