What we can learn about sleep disorders from worms

By Isabella Asselstine, Queen's University

Good sleep habits are essential to our health. A goodnights sleep supports our immune system, weight maintenance, cardiovascular health, memory and cognitive function, and a multitude of other physical and mental processes. However, sleep disorders such as narcolepsy, which causes patients to experience excessive daytime sleepiness and sudden attacks of sleep, make maintaining healthy sleep habits near impossible.

The biological cause of narcolepsy has been linked to a signaling molecule called orexin that is involved in keeping us awake. When the orexin gene (which provides the instructions to make the orexin molecule) or the gene for the orexin receptor (the protein that detects orexin) are nonfunctional, both humans and animals display narcoleptic behaviour.

Orexin is a very evolutionary old gene. So old, in fact, that we can use a tiny soil-dwelling nematode worm called Caenorhabditis elegans (C. elegans) to study it. Due to the gene’s old age and its importance in sleep regulation, versions of orexin and its receptor exist across the animal kingdom. As a result, researchers can study other organisms in order to learn more about how orexin may function in humans.

In C. elegans, a nervous system receptor called neuropeptide receptor 14, or NPR-14 for short, is thought to be equivalent to the orexin receptor in humans. In fact, the two are so similar that worms with a non-functional npr-14 gene even display narcoleptic behavior, just like what is seen in humans with a non-functional orexin receptor. This similarity makes it possible to use C. elegans to learn more about how orexin may function in humans.

The research I do is based on the idea that learning more about the npr-14 gene and its role in sleep can help us understand more about human narcolepsy. At the present, the way in which npr-14 influences sleep is still poorly understood. To bridge this gap in knowledge, my research aims to uncover where in the sleep pathway the NPR-14 receptor is located and what other biological components of sleep it interacts with.

This question can be addressed by manipulating other receptors and signaling molecules involved in sleep to either be non-functional (a knock-out mutation) or function at a higher rate than normal (an overexpression mutation). The basic idea behind these experiments is that if the NPR-14 receptor is acting in a downstream manner to another component, x, then there are a number of assumptions we can make about how introducing mutations to the npr-14 gene or the x gene may impact sleep. If the two components are indeed in the same pathway, it can be assumed that mutating both of these components would have the same effect on sleep as mutating the npr-14 gene or the x gene alone would. Furthermore, introducing an overexpression mutation in the x gene would not be sufficient to restore normal sleep if a non-functional npr-14 gene is also present. We can use this reasoning to deduce the position of the NPR-14 receptor within the sleep pathway by observing its behavior in combination with a variety of previously established components of sleep.

Successful characterization of NPR-14’s role in C. elegans sleep can provide science with an experimental system to investigate the pathology of narcolepsy. Down the line, this may allow potential therapeutics for narcolepsy to be studied and developed, allowing patients to improve their sleep behaviors and increase their overall well-being. Though this research still has a long way to go before conclusions can be drawn, I’m eager to see where this experimentation will lead and am excited to witness just how impactful these tiny worms can be in the world of sleep research.

Edited by B.G. Borowiec and A.E. McDonald. Header photo from Wikimedia Commons. Illustrations by Isabella Asselstine.