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Two birds with one cilium; PKD and Epilepsy

Genes that cause PKD could also make you more susceptible to seizures in the brain

Review written by Phillip Bokinic

PhD Candidate, Macquarie University

Cells can sense changes in their external environment through a tiny hair-like antenna known as “cilia”. Within the kidney, these sensory antennae are tightly linked to the development of polycystic kidney disease (PKD), as the disrupted genes that cause PKD are all proteins that are expressed in cilia or linked to cilia function, hence the reason PKD is part of a group of diseases called ciliopathies. Recently, a link between cilia on nerves and PKD-related genes has been found in the brain. Published in Human Molecular Genetics, Jing Zhou’s team from Harvard Medical School in Boston have discovered how two proteins found on cilia in the brain can control the activity of a nerve and critically, predispose the brain to epilepsy (1).

First, the team showed that in cilia on the nerves of the brain, a cilia protein that allows calcium to enter the cell (Polycystin-L (PCL)) is linked to a receptor (beta-2-adrenergic receptor (β2AR)), that is known to control the activity of neurons. Using a technique that identifies whether two proteins interact with each other (immunoprecipitation), the team found that PCL and β2AR do interact and likely function as a unit, suggesting that cilia can control nerve activity. They then created genetically modified (knock out) mice that lacked the PCL protein, and were able to show that these mice had less β2AR in the cilia of the brain. Critically, they also found these PCL knock out mice were more likely to have seizures, due to a massive reduction of a second messenger protein used by nerve cells called cAMP (cyclic adenosine monophosphate).

So while studies focused on the kidney have shown that cilia are involved in PKD, this is the first work to show that faulty cilia could also affect the activity of the brain. This exciting discovery shows how critical cilia are to individual cell function, be it in the kidney or the brain, and importantly, may be discovery that allows the development of new treatments for epilepsy.

1. Yao, G., Luo, C., Harvey, M., Wu, M., Schreiber, T. H., Du, Y., Basora, N., Su, X., Contreras, D., and Zhou, J. (2016) Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability. Hum Mol Genet 25, 448-458

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