Gabriel's Research Blog

Exploring the Effect of Aurora Kinase Inhibitors on Growth Suppression in a Yeast Model of ALS/FTD

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration. Neuronal death results in muscle atrophy, loss of limb motor control, and paralysis. Frontotemporal dementia (FTD) results from frontal and temporal lobe neuron death and is linked to behavioral, emotional, and communication changes. ALS and FTD lie on the same disease continuum and are genetically and clinically linked. Currently, the two diseases (ALS/FTD) have no cure, and FDA-approved treatments fail to control symptoms.

Hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common cause of familial ALS/FTD. HREs lead to the formation of dipeptide repeat proteins, which aggregate into inclusions in the neurons of ALS/FTD patients. Exploiting a yeast ALS/FTD model overexpressing the dipeptide repeat protein PR50, comprising 50 repeats of the dipeptide Proline-Arginine on a galactose-inducible promoter, we previously discovered that overexpression of PR50 is associated with increased levels of Histone H3 Serine 10 phosphorylation (H3S10ph). Furthermore, we previously found that knockdown of Ipl1, the yeast homolog of Aurora B Kinase responsible for H3S10ph, leads to decreased H3S10ph levels and growth rescue in yeast overexpressing PR50.

Histone modifications are highly accessible targets for pharmaceutical intervention. Therefore, with the aim of preventing H3S10 phosphorylation increases and ameliorating PR50 toxicity without the need for genetic manipulation, we investigated the effects of chemical inhibition of the yeast aurora kinase Ipl1 in cell survival in the context of PR50 overexpression. We performed a virtual screen for inhibitors of Ipl1 using the computational modeling software Maestro and selected the inhibitor Barasertib to perform experimental work on the chemical inhibition of Ipl1. We performed serial dilution growth assays on PR50 yeast in the presence of the Aurora B Kinase inhibitor drug Barasertib at varying concentrations. Upon treatment, we observed changes in H3S10ph by western blot analysis. Through inhibition of Ipl1 and growth rescue of PR50 yeast, we aim to establish potential epigenetic drugs in the treatment of neurodegenerative disease.