Yes. First they would need to isolate the huntintin protein and determine its 3-demensional shape and its sequence of amino acids. Then through a series of trial and error they would be able to use grid-computing to try and figure out what sequences would potenitally bind the huntingtin protien. The antibody would need to be able to be recognized by the bodies immune system for degredation. A potential mechanism for correcting the overexpression of the huntintin protein would be to use a gene therapy by way of intrabodies. To successfully administor these intrabodies the intrabody would need to be sequenced and placed into a vessel would have a target in the basal ganglia and also be able to pass through the blood-brain barrier. If this was able to be accomplished the intrabody gene would need to be inserted into the host DNA and expressed. If the gene was able to be expressed then it could recognize and bind the huntingtin protein to then undergo regulation.
2. In an evolutionary sense, why is it informative to study Huntington’s and its implications in mice?
Its important to study the evolutionary aspect of huntingtons disease because we can better understand how a disease comes about due to a mutation. It is also beneficial to know how the disease can be spread to offspring or other individuals through generations. In Huntington’s Disease we know that the disease is autosomal dominant which basically means that the inheritance of one allele can result in the disease. This combined with a late onset is why the disease has not felt the effects natural selection. Selection can only act on phenotypes it can see. Typically an individual with HD would most likely have reproduced before the onset of noticeable symptoms and the disease can proliferate.
It’s important to understand its implications in mice because they are a commonly used because of their genetic and physiological similarities to humans. In addition they can be used for manipulation to test treatments or other effects of potential therapies. They reproduce quickly and in high number. In addition they are relatively easy to manage in a research lab.
3. Apply Darwin’s four postulates to the traditional view of neuron selection.
Within an individual’s brain tissues, variation is present in the genetic makeup of neurons—or more accurately, the genes that code for neuronal products vary. These genetic differences underlie both phenotypic and behavioral variation of the neuron. Within the somatic line, as neurons undergo mitotic division, they pass on their genetic makeup to daughter neurons (including any mutations they have accrued). This results in one kind of cell that produces multiple genotypes, a process termed genetic mosaicism.
Because neurons vary and that variation is heritable, there exists a potential difference in neuronal performance. In short, some neurons are better at doing their job than others, and these differences can result in differential fitness between cells within an individual’s brain tissues. For example, a line of neurons that has acquired a mutation that leads to cell death will have a lower reproductive success than other healthy neurons. Theoretically, the “adapted” neurons would then become more numerous and shift the population of cells towards its own genotype. Important to neuron selection is the concept that neurons exhibit genetic variation, that variation is inherited (mitosis), neurons experience differential reproductive success, which together results in the evolution of cell populations within brain tissue.
4. Now add the selective pressure of MSH3 and instability and describe how this violates the assumptions we have made in class about “important” mutations.
Huntington’s disease is caused by a mutant allele that possesses an excess triplet repeat sequence of CAG. A threshold of 36> CAG repeats has been correlated with the onset of the disease. As the CAG repeats are translated, they create excess glutamine, which accumulate and cause the improper folding of the Huntington protein (a protein required by all cells). Mutant proteins then sequester important proteosomes required for cell function. This in turn results in neuronal cell death, specifically in the striatum.
Similar to other diseases that are the product of an excess triplet repeats, the sequence expands with every somatic and gametic division. Unlike ordinary mutations, this implies carriers of the mutant Huntington allele will not pass on the same allele they inherited—it will be expanded. Different from other mutations, the Huntington mutant continuously accrues new and predictable mutations. Neurons in different parts of the brain exhibit variable repeat lengths (genetically differentiated neuronal populations evolve). The CAG repeat grows with every division, somatic or gametic. This is known as instability.
One of the most compelling explanations for why this happens involves the role played by MSH3—a DNA mismatch repair gene. Under normal conditions, MSH3 replaces mismatched base pairs: it acts to eliminate mutations or increase fidelity during replication. However, because the mutant Huntington sequence causes a CAG hairpin loop to form, MSH3 binds to the CAG hairpin, undergoes a biochemical change, and promotes expansion, rather than correcting the mismatches. Usually a positive force, in the case of the mutant Huntington’s gene, MSH3 has become an accomplice in the perpetuation of this mutation. What makes the Huntington mutation different from other mutations concerns a kind of independence it experiences from selection. In the case of Huntington’s, genetic variability is largely dependent on specific chemical conditions—the presence of MSH3. Both of these factors differentiate it from other typical mutations.
5. Is Huntington’s Disease itself subject to selection? Why or why not?
It is more subject to artificial selection because if the disease is diagnosed before reproduction it decreases the fitness of the gene. In past the onset of symptoms was after reproduction would likely occur and the disease was already passed on to offspring. Natural selection can only act on phenotypes that it can see. If the onset is commonly after reproduction then natural selection would ineffective.
6. Why is it important to study protein folding/misfolding in Huntington’s, even though we know its cause (trinucleotide repeats)?
It is known that due to the trinucleotide repeats in the Huntington gene, an excess of Huntington protein builds up in the neurons of the Basal Ganglia, which proves to be detrimental to the normal functioning of those neurons. The more we can learn about the actual three dimensional shape and the folding/misfolding of the excess Huntington protein, a therapy could be developed that either alters the Huntington protein to a less toxic form or degrades excess amounts of the Huntington protein in the neurons that are affected by the mutated Huntington gene. In short, while a mutation in the Huntington gene is the actual source of the disease, methods could be developed to help "silence" the effects of the gene by regulating the amount of Huntington protein that is produced. So being able to understand the folding of the Huntington protein and the effects of misfolding it would go a long way in finding a possible cure or treatment for Huntington's disease.
