I’m submitting abstract for poster presentation. I contacted [email protected] – they gave me permission to submit late.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and lower motor neurons. While the cause of ALS is unknown, the most common genetic risk factor for ALS is an expansion of a hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9orf72) gene. This repeat expansion leads to the expression and accumulation of 5 different dipeptide repeat proteins; however, it is unknown how these dipeptide repeats contribute to disease pathogenesis. There is evidence that neuronal nuclear dysfunction, such as abnormal size and shape, occurs in ALS. Our data shows that two of these C9orf72 dipeptide repeats, poly-RP and poly-RG, are cytotoxic when expressed in neuronal cells, producing nuclear and cellular pathological phenotypes. To explore a potential mechanism underlying the development of these pathologies, we focused on a signaling pathway that is critical for regulating nuclear processes. Aurora B kinase is a serine/threonine kinase that localizes to chromosomes and has been reported to play an important role in both mitosis and cytokinesis in differentiating cells, as well as neurite outgrowth in neurons. Based on its predominantly nuclear localization and functions, our hypothesis is that an impairment in Aurora B kinase activation contributes to the development of both nuclear pathologies associated with the poly-RP and poly-RG dipeptides. To address this hypothesis, we transfected rat primary cortical neurons from 18-day embryos with expression plasmids containing the C9orf72 dipeptides. We found that there are alterations in Aurora B kinase levels in cells expressing the poly-RP and poly-RG dipeptides, specifically a decrease in cells expressing the poly-RP dipeptide and an increase in cells expressing the poly-RG dipeptide. Treating primary cortical neurons that were transfected with the dipeptides with a selective Aurora B kinase inhibitor, AZD1152, resulted in a decrease in neurite length in cells expressing the poly-RP dipeptide and an increase in neurite length in cells expressing the poly-RG dipeptide, suggesting that Aurora B kinase plays a role in axonal processes. Our findings indicate that alterations in Aurora B kinase may be involved in the development of pathological phenotypes in C9orf72-associated ALS, perhaps establishing an overall mechanism of neurodegeneration.