BackgroundHuntington’s disease is inherited as an autosomal dominant disease that givesrise to progressive, elective (localized) neural cell death associated withcholeric movements (uncontrollable movements of the arms, legs, and face) anddementia. It is one of the more common inherited brain disorders. About 25,000Americans have it and another 60,000 or so will carry the defective gene andwill develop the disorder as they age. Physical deterioration occurs over aperiod of 10 to 20 years, usually beginning in a person’s 30’s or 40’s. The geneis dominant and thus does not skip generations. Having the gene means a 92percent chance of getting the disease.
The disease is associated with increasesin the length of a CAG triplet repeat present in a gene called ‘huntington’located on chromosome 4. The classic signs of Huntington disease are progressivechorea, 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’sdisease. Part of the research was to analyze cerebral deletion levels in thetemporal and frontal lobes. Research hypothesis: HD patients have significantlyhigher mtDNA deletionlevels than agematched controls in the frontal and temporallobes of the cortex.Order now
To test the hypothesis, the amount of mtDNA deletion in 22HD patients brains was examined by serial dilution-polymerase chain reaction(PCR) and compared the results with mtDNA deletion levels in 25 aged matchedcontrols. Brain tissues from three cortical regions were taken during an autopsy(from the 22 HD symptomatic HD patients): frontal lobe, temporal lobe andoccipital lobe, and putamen. Molecular analyses were performed on genetic DNAisolated from 200 mg of frozen brain regions as described above. The HDdiagnosis was confirmed in patients by PCR amplification of the trinucleotiderepeat in the IT 15 gene. One group was screened with primers that includedpolymorphism and the other was screened without the polymorphism. After heatingthe reaction to 94 degrees C for 4 minutes, 27 cycles of 1 minute at 94 degreesCand 2 minutes at 67 degrees C, tests were performed.
The PCR products weresettled on 8% polyacrylamide gels. The mtDNA deletion levels were quantitatedrelative to the total mtDNA levels by the dilution-PCR method. When thepercentage of the mtDNA deletion relative to total mtDNA was used as a marker ofmtDNA damage, most regions of the brain accrued a very small amount of mtDNAdamage before age 75. Cortical regions accrued 1 to 2% deletion levels betweenages 80-90, and the putamen accrued up to 12% of this deletion after age 80. Thestudy presented evidence that HD patients have much higher mtDNA deletionlevelsthan agematched controls in the frontal and temporal lobes of the cortex.
Temporal lobe mtDNA deletion levels were 11 fold higher in HD patients than incontrols, whereas the frontal lobe deletion levels were fivefold higher in HDpatients than in controls. There was no statistically significant difference inthe average mtDNA deletion levels between HD patients and controls in theoccipital lobe and the putamen. The increase in mtDNA deletion levels found inHD frontal and temporal lobes suggests that HD patients have an increase mtDNAsomatic mutation rate. Could the increased rate be from a direct consequence ofthe expanded trinucleotide repeat of the HD gene, or is it from an indirectconsequence? Whatever the origin of the deletion, these observations areconsistent with the hypothesis: That the accumulation of somatic mtDNA mutationserodes the energy capacity of the brain, resulting in the neuronal loss andsymptoms when energy output declines below tissue expression thresholds. (Neurology, October 95) Treatments Researchers have identified a key proteinthat causes the advancement of Huntington’s after following up on the discoverytwo years ago of the gene that causes this disorder.
Shortly after theHuntington’s gene was identified, researchers found the protein it produces, alarger than normal molecule they called huntingtin that was unlike any proteinpreviously identified. The question that they did not know was what either thehealthy huntingtin protein or its aberrant form does in a cell. Recently, a teamfrom Johns Hopkins University found a second protein called HAP-1, that attachesto the huntingtin molecule only in the brain. The characteristics of this secondprotein has an interesting feature- it binds much more tightly to defectivehuntingtin than to the healthy from, and it appears that this tightly boundcomplex causes damage to brain cells. Researchers are hoping to find simpledrugs that can weaken this binding, thereby preventing the