Huntington’s Disease Essay, Research Paper

Huntington’s Disease

Background

Huntington’s disease is inherited as an autosomal dominant disease that gives

rise to progressive, elective (localized) neural cell death associated with

choleric movements (uncontrollable movements of the arms, legs, and face) and

dementia. It is one of the more common inherited brain disorders. About 25,000

Americans have it and another 60,000 or so will carry the defective gene and

will develop the disorder as they age. Physical deterioration occurs over a

period of 10 to 20 years, usually beginning in a person’s 30’s or 40’s. The gene

is dominant and thus does not skip generations. Having the gene means a 92

percent chance of getting the disease. The disease is associated with increases

in the length of a CAG triplet repeat present in a gene called ‘huntington’

located on chromosome 4. The classic signs of Huntington disease are progressive

chorea, rigidity, and dementia, frequently associated with seizures. Studies &

Research Studies were done to determine if somatic mtDNA (mitochondria DNA)

mutations might contribute to the neurodegeneration observed in Huntington’s

disease. Part of the research was to analyze cerebral deletion levels in the

temporal and frontal lobes. Research hypothesis: HD patients have significantly

higher mtDNA deletionlevels than agematched controls in the frontal and temporal

lobes of the cortex. To test the hypothesis, the amount of mtDNA deletion in 22

HD patients brains was examined by serial dilution-polymerase chain reaction

(PCR) and compared the results with mtDNA deletion levels in 25 aged matched

controls. Brain tissues from three cortical regions were taken during an autopsy

(from the 22 HD symptomatic HD patients): frontal lobe, temporal lobe and

occipital lobe, and putamen. Molecular analyses were performed on genetic DNA

isolated from 200 mg of frozen brain regions as described above. The HD

diagnosis was confirmed in patients by PCR amplification of the trinucleotide

repeat in the IT 15 gene. One group was screened with primers that included

polymorphism and the other was screened without the polymorphism. After heating

the reaction to 94 degrees C for 4 minutes, 27 cycles of 1 minute at 94 degreesC

and 2 minutes at 67 degrees C, tests were performed. The PCR products were

settled on 8% polyacrylamide gels. The mtDNA deletion levels were quantitated

relative to the total mtDNA levels by the dilution-PCR method. When the

percentage of the mtDNA deletion relative to total mtDNA was used as a marker of

mtDNA damage, most regions of the brain accrued a very small amount of mtDNA

damage before age 75. Cortical regions accrued 1 to 2% deletion levels between

ages 80-90, and the putamen accrued up to 12% of this deletion after age 80. The

study presented evidence that HD patients have much higher mtDNA deletionlevels

than agematched controls in the frontal and temporal lobes of the cortex.

Temporal lobe mtDNA deletion levels were 11 fold higher in HD patients than in

controls, whereas the frontal lobe deletion levels were fivefold higher in HD

patients than in controls. There was no statistically significant difference in

the average mtDNA deletion levels between HD patients and controls in the

occipital lobe and the putamen. The increase in mtDNA deletion levels found in

HD frontal and temporal lobes suggests that HD patients have an increase mtDNA

somatic mutation rate. Could the increased rate be from a direct consequence of

the expanded trinucleotide repeat of the HD gene, or is it from an indirect

consequence? Whatever the origin of the deletion, these observations are

consistent with the hypothesis: That the accumulation of somatic mtDNA mutations

erodes the energy capacity of the brain, resulting in the neuronal loss and

symptoms when energy output declines below tissue expression thresholds.

(Neurology, October 95) Treatments Researchers have identified a key protein

that causes the advancement of Huntington’s after following up on the discovery

two years ago of the gene that causes this disorder. Shortly after the

Huntington’s gene was identified, researchers found the protein it produces, a

larger than normal molecule they called huntingtin that was unlike any protein

previously identified. The question that they did not know was what either the

healthy huntingtin protein or its aberrant form does in a cell. Recently, a team

from Johns Hopkins University found a second protein called HAP-1, that attaches

to the huntingtin molecule only in the brain. The characteristics of this second

protein has an interesting feature- it binds much more tightly to defective

huntingtin than to the healthy from, and it appears that this tightly bound

complex causes damage to brain cells. Researchers are hoping to find simple

drugs that can weaken this binding, thereby preventing the disease to progress

any further. In other Huntington-related research, scientists have found where

huntingtin protein is localized in nerve cells, a step closer to discovering its

contribution toward Huntington’s. A French team reported that they have

developed an antibody that attaches itself to the defective protein in

Huntington’s and four other inherited diseases. This finding may lead to

identifying the defects in a variety of others unexplained disorders. The

identification of the gene an the huntingtin protein promised to be a major

breakthrough in tracing the causes of Huntington’s, but that promise has so far

been delayed. The protein of Huntington is unlike any other protein known making

it difficult for researchers to guess its role in a healthy cell. However, this

has not stopped researchers from trying to find a possible cure for HD. Effects

on Society By finding possible drugs to weaken the binding of the HAP-1 protein,

researchers can provide society an incredibly sophisticated, but quick and easy

wasy to screen for new treatments. One of the biggest arguments for genetic

testing, even when there isn’t any cure or treatment to offer the patient, is

financial planning. If you know that you’re probably going to be disabled and

unable to work before reaching 50, you can plan for it. But what if your income

doesn’t allow for it? This demonstrates the importance for continuous research

on HD. Overview of the Two Articles Both articles concentrate on HD’s protein

causing affect. There is no doubt between the two that HD is an inherited

mutation. The Neurology articles explains how HD patients have much higher

deletion levels than agematched controls in the frontal and temporal lobes of

the cortex, whereas the article from Times Medical Writer focuses on a possible

treatment resulting from a finding of a second protein called HAP-1, that binds

itself to the huntingtin molecule only in the brain. Both conclude that HD is a

mutation that causes damage to brain cells further in a person’s life.