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Eukaryon

Emergency PSA on PIAS1

Maisie Pritchett
Lake Forest College
Lake Forest, Illinois 60045

Over the years, scientists have made significant progress in the field of neurodegenerative disease research. It is now fairly well known that insoluble protein aggregations are an integral part of neurodegenerative disease pathology1

            This is true as well for Huntington’s disease (HD), a familial, autosomal dominant disease, affecting around 1 in 10,000 Americans at any time7. In HD, huntingtin protein (HTT) aggregates both in and outside the nucleus of basal ganglion neurons, leading to neuron degeneration8. This loss of neurons leads to erratic uncontrolled movement and impaired cognitive function2.

            Huntington’s disease is caused by an expansion mutation3. Normally, nucleotide bases code for end terminals that cause a cell to stop adding glutamine together to make a protein chain. In HD, the protein chain has a large number of CAG repeats that make a large chain prone to misfolding3.

            This misfolded HTT has been shown to aggregate within neurons. Until recently, scientists were not sure how HTT was sticking together and forming insoluble aggregations3. In a paper by Ochaba J. et al., titled PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes in Vivo, researchers propose that the protein PIAS1 could be responsible for activating a reaction pathway, eventually leading to the formation of insoluble protein aggregations.

The paper by Ochaba et al. explains that the PIAS1 protein catalyzes an HTT SUMOylation pathway. SUMOylation is the process by which small ubiquitin-like proteins are added onto an existing protein, causing it to become larger and changing its overall shape4. This process that takes place all over the body serves many functions and is usually harmless or even helpful5,6 However, in the case of HTT SUMOylation, this change in shape has very harmful consequences, causing the protein polymers to stick together and form insoluble aggregations that can’t be broken-down by the body. These hinder cellular function and eventually lead to cell death.

            How can we decrease or slow the progression of disease pathology through altering this pathway? This is the question these researchers were trying to answer when they hypothesized that decreasing the amount of PIAS1 would be beneficial to patients with Huntington’s disease. They concluded that lessening the catalyst for SUMOylation of HTT would prevent these proteins from forming insoluble aggregations, allowing the cells to function normally, and protecting them from the progression of disease symptoms.

            In order to test their hypothesis, this group of researchers needed to create eight mouse models to represent their experimental and control groups. Their objective was to see what would happen when PIAS1 was under and overexpressed, to determine whether or not there was a change in disease progression. The first four mouse models were used to measure the effects of under-expression in disease and wild type mice. The wildtype and disease control mice did not have altered levels of PIAS1, while the experimental wildtype and disease mice were injected with a strand of miRNA that would block some of the mouse’s PIAS1 protein from being made. These mice are called knock-down mice and express less PIAS1.The next four mice followed the same pattern; however, the genes in the experimental mice were changed so that there was a higher than normal amount of PIAS1 expressed.

            After the model mice were made, the researchers had the means to run experiments to test their hypothesis. The first thing they needed to see was whether or not the number of insoluble aggregations decreased congruently with PIAS1. They discovered that while wildtype mice were not affected by a reduction of PIAS1, the mice with Huntington’s disease were shown to have significantly fewer aggregations when they had a reduced amount of PIAS1 and a significantly higher amount. This finding showed that PIAS1 modulation could successfully control aggregation formation in HD.

            This is an exciting discovery because it is believed that aggregations lead to the development of many of the observable symptoms in HD, such as loss of motor control and the deterioration of the basal ganglia. It is still unknown if reducing aggregations through decreasing PIAS1 would show a noticeable difference in the overall progression of the disease.

            To determine the overall effect of PIAS1 reduction, Ochaba et al. measured and compared the physical abilities and amount of neuron loss in the basal ganglia of all eight types of mice.

            The mice were subjected to a series of tests to measure their grip strength, climbing ability, and balance. In every test of physical ability, the mice with a reduced amount of PIAS1 and fewer aggregations performed better than both the wild type mice with HD and no change to their PIAS1 levels, and the mice with an overexpression of PIAS1. This shows that reducing the levels of PIAS1 in mice with Huntington’s disease improves their ability to control their movement and coordination.

            Finally, the researchers found, consistent with their other results, that there was less neurodegeneration or cell death in the mice with reduced levels of PIAS1.

            All three of these findings support the hypothesis Ochaba et al. presented in their paper and have opened the path for a possible leap in the treatment of Huntington’s disease. Now that it is known that reducing levels of PIAS1 can reduce the symptoms of Huntington’s disease, PIAS1 targeted genetic modification can be looked to as a possible treatment. Since Huntington’s disease is an inherited disease1, it is possible that children of people with HD who are at a high risk of developing the disease1 could have their PIAS1 levels suppressed in order to avoid or reduce the effects of the disease.

 

References:

  1. Saudou. S. Humbert., Neuron 89, 910 (2016). http://www.cell.com/neuron/fulltext/S0896-6273(16)00096-9
  2. Huntingon’s Disease Society of America (2018) web. http://hdsa.org/what-is-hd/
  3. Grima et al., Neuron 94, 93 (2017). http://www.cell.com/neuron/fulltext/S0896-6273(17)30206-4
  4. Gareau. C. Lima., Na Rev Mol Cell Biol, 11, 861 (2010). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079294/
  5. com Sumoylation, web. https://www.nature.com/subjects/sumoylation
  6. Ciechanover. P. Brundin., Neuron. 40, 427, (2003). http://www.cell.com/neuron/fulltext/S0896-6273(03)00606-8
  7. Liou., Huntington’s Disease Outreach Project for Education, at Stanford, Genetics. (2010). http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/population-genetics-and-hd/#what-is-the-frequency-of-hd-around-the-world

S. Liou., Huntington’s Outreach Project for Education, at Stanford, Neurobiology. (2010). http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/the-basic-neurobiology-of-huntingtons-disease-text-and-audio/#what-parts-of-the-brain-are-most-affected-in-hd-patients

 

Pritchet Fig 1

 

In their research, Ochaba et al. found that reducing the protein PIAS1 prevents the SUMOylaiton of HTT and in turn reduces the number of insoluble aggregations. This decrease in aggregations leads to greater control of movement and decreased neuronal loss in the Basal ganglia than in wildtype mice with Huntington’s disease.

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