Questions About Huntington's

1. The PNAS paper entitled “Potent inhibition of huntingtin aggregation and cytotoxicity by a disulfide bond-free single-domain intracellular antibody” (Colby et al. 2004) describes a potential treatment that uses “intrabodies” (intracellular antibodies) to bind the toxic fragment of the huntingtin protein and inactive it or prevent its misfolding. Could this treatment be modeled using grid-computing? The intrabody would have to be introduced using gene therapy. How would this work?

Grid-computing can be used to model potential treatments that use “intrabodies” to bind the toxic fragment of the huntingtin protein and inactivate it or prevent its misfolding. There are two possible ways that gene therapy could be either to inactive or prevent misfolding. The first way requires the introduction of the intrabody to the toxic fragment of the protein that has been misfolded. The intrabody would be placed on the misfolded protein and would correct for the errors that lead to Huntington’s disease. The second way would require the placement of the intrabody onto the protein prior to any potential misfolding. This method would prevent the problem of misfolding before it had a chance to occur. Grid-computing would act as a simulation of the protein folding and configure how likely it would be that these treatments would be effective. The data collected across these shared computer systems would provide information regarding when treatments would need to be used in order to stop Huntington’s disease in its tracks. The information could tell researchers whether this form of gene therapy would be worthwhile in human beings.

2. In an evolutionary sense, why is it informative to study Huntington's and its implications in mice?

It is informative to study Huntington’s and its implications in mice because of their close evolution relation to humans. Their body plans, physiology, and genome share many of the same features. It is evident that mice and humans share orthologous genes, meaning homologous sequences (from a recent common ancestor) that have been separated by a speciation event. Due to these genes, the neurons that are affected by Huntington’s in mice most likely follow similar pathways and probably function in the same ways in humans. A study by Gonitel et al., 2008 demonstrates this similarity by examining how mutations form repetitive CAG sequences which creates unique neuronal populations in both mice and HD patients. It is also shown how both mice and humans share the MSH3 gene which differentiates neurons from nonneuronal cells.

3. Apply Darwin's four postulates to the traditional view of neuron selection.

1. Individuals within a species are variable.

   -In an individuals body there are several different kinds of neurons

2. At least some of these variations are hereditary

   -Some neurons will be passed on to future generations, and if the neurons are infected with HD, these defective genes will be passed on

3. In every generation there are more offspring produced than survive

   -The favorable neurons will outlive the nonfavorable neurons since there are not enough resources for all of them to survive

4. Natural Selection operates on populations

   -The neurons that survive are more adaptable to their environment and have higher fitness. The neurons that have been infected by Huntington’s keep repeating and changing so that they continue to survive in their environment.

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.

MSH3 accounts for the instablility in Huntington's mice, while the factors that cause the cell-specific differences in CAG repeat instability are unknown. Nothing is known about the distribution of MSH3 in the brain. However, cells withouth MSH3 are unable to cause CAG repeat size in adults. Therefore, this protien accounts for the expansion of the sequences. This violates the assumptions we have made about important mutations because mutations must occur by reproductive age in order to be passed on to future generations. But the repeat sequence cannot be modulated in adulthood in cells that lack MSH3.

5. Is Huntington’s Disease itself subject to selection? Why or why not?

Huntington’s disease largely escapes the pressures of selection because the onset of the disease, in most cases, does not appear until the individual is past reproduction age. Late-onset Huntington’s is especially immune to selection because the alleles are almost invisible to the selection process because of the age when Huntington’s hits. Although Huntington’s is a deadly disease and the CAG repeats are almost always deleterious the alleles still get passed on to future generations. The only way selection could affect Huntington’s is because of its anticipation factor. It has been shown that an increase in the number of repeats also increases the severity and onset of symptoms. If the analogous repeat lengths were to be inherited there would be a difference of several decades in age of onset, and this would be strongly selected against if the age were to be before reproduction age. Although it is very unlikely that selection could eliminate this disease because it is mutation based and some get the disease without any family history of it.

6. Why is it important to study protein folding/misfolding in Huntington’s, even though we know its cause (trinucleotide repeats)?

Studying protein misfolding is very important in searching for a cure for Huntington’s. Although the cause of Huntington’s is already known a cure has still yet to be found and the answer may be found in dealing with the aggregate proteins. Figuring out why the repeats cause the proteins to clump may lead to a drug which eliminates this effect. Also, one of the factors for the pathogenicity of the disease is the cellular context. The instability of the disease is largely due to the misfolding of proteins.