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Synthetic rescue: discovering therapeutic targets for ALS

Jeong Yeol Lee, 4th year PhD, University of Exeter

BACKGROUND:

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Amyotrophic lateral sclerosis (ALS) is one of the most common motor neuron diseases. It is also known as Lou Gehrig’s disease, and it is caused by the gradual death of motor neurons in the brain and spinal cord. ALS symptoms include muscle twitching, limb weakness, and slurred speech. The majority of patients suffer from this condition between the ages of 60 to 85. Although the rate of illness progression varies, it is usually fatal within 3-5 years of diagnosis. Unfortunately, there are just a few treatment choices to treat ALS. Palliative care is currently the best option for ALS; therefore, new therapies to treat ALS are needed.

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When two genes are mutated, a phenomenon known as genetic interaction takes place. This mutation causes a phenotype that is different from the expected outcome based on each gene mutation alone. A positive genetic interaction occurs when two mutations combine to produce a phenotype that is less severe than either mutation would have on its own. A modifier gene (potential drug target) that interacts favourably with ALS-associated mutants can be found via positive genetic interaction. This approach is called synthetic rescue. Finding a modifier gene that interacts positively with ALS-associated mutants is the aim of the study, as it may point to a potential target for therapy.

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METHODOLOGY:

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In this project, I used Drosophila S2R+ cells, known as fruit fly cells. First, I made mutants of ALS-associated genes to insert the mutant genes into fruit fly cells. GFP (green fluorescent protein) and one of the ALS-associated mutant genes were inserted into fruit fly cells. After confirming that the ALS-associated mutants were in the cells, the intensity of the GFP light was measured to determine how many cells were alive by using a flow cytometer.

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RESULTS:

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Three ALS-associated genes were examined in this project. To begin, wild-type of the ALS-associated genes were introduced to determine their toxicity to fruit fly cells. Then, it was discovered that FUS is too toxic to cells, making further research impossible. Two SOD1 mutants and three TDP43 mutants are appropriate for the viability measurement technique established in the SOD1 and TDP43 fruit fly models. I created fruit fly cell models and then used pooled kinase library screening to identify kinases that could be used as potential drugs. To find out whether genes are up-/down-regulated in fruit fly cells when wild-type of ALS-associated genes and their mutants are present, I performed RNA-seq.

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FUTURE WORK:

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I am currently working on my thesis writing, with a three month deadline in sight. In the future, I hope to further my proficiency in drug discovery.

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FUNDED BY:

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University of Exeter

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CONTACT:

JY_Synthetic rescue.png

Figure 1. Concept of synthetic rescue. Genetic interaction between mutated ALS-associated genes with a modifier gene leads to viability rescue.

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Figure 2. Human-originated protein expression in Drosophila S2R+ (fruit fly) cells.

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Lee Jeong Yeol

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