CR #1 Flashcards
The authors state that 8-oxo-G glycosylase is not essential for life in mice. Why might this not necessarily hold true for humans?
Humans and rats differ drastically in respect to their lifespans. This means that a repair mechanism for a mouse might not be as necessary of a function since a mouse has a lifespan of 2 years. Therefore, repairing DNA might be a rare occurrence. Humans live a lot longer, so more complications arise as the body decays in later years. This means that DNA repair mechanisms are a lot more important to making sure that a person ’s DNA is not damaged as they age.
What diseases in humans are due to a deficiency for the base-excision pathway?
A deficiency for the base-excision pathway could result in cancer, as a study that the base excision repair cells could be a source of pre-cancerous cells. As well, a defect in the base-excision pathway was found in individuals with Alzheimer’s disease, as well as in people with amnestic mild cognitive impairment.
Base-excision repair is not the only DNA repair mechanism known to result in expansion of trinucleotide repeats. Describe another DNA repair mechanism and how it affects the expansion of trinucleotide repeats.
Other DNA repair mechanisms that effect the expansion of trinucleotide repeats are mismatch repair, homologous recombination and non-homologous end joining. Non-homologous end joining uses a non-homologous chromosome to repair double stranded breaks in DNA. This is done using microhomologies, which guide the repair. Microhomologies are short homologous DNA sequences. Similar to base-excision, a strand slippage occurs during the DNA synthesis step and results in a trinucleotide repeat expansion.
What is the basis and biological rationale for the therapeutic approach used in this paper?
The approach in this paper is the use pharmacological treatment with XJB-5-131 which is a mitochondrial-targeted scavenger of reactive oxidase. XJB-5-131 reduces the oxidative DNA substrate for OGG1 functions as an enzyme to remove oxidized bases on DNA.It is a pharmacological inhibitor that shortens or prevents the lengthening of the repeat tracks. Thus, reducing oxidative damage. When this was used in mice affected with Huntington’s disease, it suppressed motor decline and inhibited somatic expansion.It was determined that the decrease of somatic expansion was what improved motor performance.
Name and describe two additional diseases that may be candidates for this pharmacological intervention.
Additional diseases that can be candidate for this pharmacological intervention includes fragile x syndrome which is another triplet expansion disease. The normal gene contains 5-55 copies of CGG in FMR1 gene, however, affected individuals have over 200 repeats. Thus, the approach of reducing the somatic expansion can provide a therapeutic means for treating this disease.
Myotonic dystrophy is also another disease that can potentially be treated with this approach. Myotonic dystrophy is included in a group of inherited disorders known as muscular dystrophies. This disease is caused by (CTG)n repeats and is known to cause progressive muscle weakness. Recently, a second from of this disease, myotonic dystrophy type 2 (DM2) was recognized. DM2 is determined to be caused by repeat expansion specifically CCTG repeat. Thus, since expansion is involved in this disease, then this pharmacological intervention can be used as an intervention.
What other therapeutic approaches have been tried unsuccessfully to treat patients affected with Huntington’s disease?
In other therapeutic approach, the onset of Huntington’s disease is understood as a disease that depends on the length of the inherited allele. It is believed that the potential of the disease is established at birth and the diseases also rises from years of toxic effects caused by a mutant protein or RNA. However, this therapeutic approach has not been successful because it is restricted to just inhibiting the effects of toxic protein-protein or RNA-protein interactions. It implies that the onset of the disease is largely due the inherited repeat and that it does not change.
In older mice, the differences in motor ability became less evident between mice mutant for Ogg and wildtype mice. How do the authors explain this observation?
The authors concluded that when that when mice were 40 weeks old or older, somatic expansion lost its dependence on OGG1. They explained that it is most likely due to the “action of other glycosylases or nucleotide excision repair enzymes that back-up OGG1 in removing oxidative DNA damage as the number of lesions rises”. The authors also noticed neuron decline and inclusion in both Hdh(Q150/Q150)/OGG1(-/-) and Hdh(Q150/Q150)/OGG1(+/+) compared to the wild group between the ages of 50 and 100 weeks. From this they concluded somatic expansion continued above forty weeks. But the distinction between genotypes and the effects of the inherited and somatic expansions were unresolved.
Which tissue showed the largest repeat tract length? How does this relate to what is known about the area of the brain that is greatest affected by Huntington’s disease?
The tissue in the brain that showed the largest repeat tract length is the striatum. Based on the scientific literature, the basal ganglia, which is composed of the caudate and the putamen (together known as the striatum) is responsible for motor movement of the body. The basal ganglia is the most effected area of the brain in Huntington’s disease. In people with Huntington’s disease, the basal ganglia is actually smaller normal due to death of neurons in this region from the progression of the disease. Based on this study, it makes sense that the area of the brain responsible for motor movement is most effected by somatic expansion since in the mice studied, loss of motor function was so prevalent.
