Melatonin alterations in Huntington's disease help explain trouble with sleep

Many people with Huntington’s disease have problems sleeping. Sleep-wake cycles are controlled in part by melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep, a hormonehormone Chemical messengers, produced by glands and released into the blood, that alter how other parts of the body behave that makes you drowsy at bedtime. Scientists in London measured melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels in HD patients, gene carriers, and unaffected individuals and found changes in the levels and timing of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep release. This could help to explain the sleep disruptions that occur in HD.

Sleep can be elusive

If you’ve ever been in bed with your mind racing, wishing for sleep, you know that slipping into dreamland is far less simple than it seems. In fact it requires a lot of complex coordination by different parts of the brain to get your body in tune with the darkening world, leaving you drowsy enough to fall asleep and restful enough to stay that way till morning.

We know that people with Huntington’s disease sleep poorly: nearly 80% of Huntington’s disease sufferers experience sleep disturbances. These can include an increase in the length of time it takes to fall asleep, changes in what the brain is doing during sleep, and decreases in the amount of truly restful sleep. It’s not well understood why these disturbances occur in HD, but a new study highlights changes in levels of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep, a chemical that regulates sleep and wakefulness in relation to the rising and setting of the sun.

Brain control of sleep

Our predisposition for nighttime sleep and daytime activity is just one of many circadiancircadian a circadian rhythm is something that repeats every day, like the body's sleep-wake cycle rhythms, a term that refers to anything that changes within our bodies on a 24-hour cycle, and can be synchronized with what’s happening in our environment. Lots of human behaviors are rhythmic or change predictably over the course of a day. Not only sleep and alertness, but also digestion, body temperature, and the immune system change depending on what time it is. We’ve talked about sleep and circadian rhythms in Huntington’s disease before..

These rhythms are overseen by a brain region called the suprachiasmatic nucleussuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms, or SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms. The SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms acts as the brain’s timekeeper, coordinating the body’s activities over the 24-hour day. Neuronsneuron Brain cells that store and transmit information in the SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms are perfectly situated to communicate with cells from the eyes that describe how much light there is in the environment. With this information, the SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms can send out a message to other brain and body areas telling them what they need to do to keep their cycles running smoothly.

Because of the resulting circadiancircadian a circadian rhythm is something that repeats every day, like the body's sleep-wake cycle rhythms, levels of all kinds of substances made by the body can fluctuate normally with the amount of light outside, and melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep is an important one. MelatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep is a hormonehormone Chemical messengers, produced by glands and released into the blood, that alter how other parts of the body behave, a chemical messenger that circulates in the blood. It is produced by an organ deep in the center of the brain called the pineal glandpineal a gland in the brain that produces the hormone melatonin. As the sun begins to go down, the SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms senses the change in light and sends a message to the pineal glandpineal a gland in the brain that produces the hormone melatonin to start secreting melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep. MelatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep helps to regulate sleep cycles by causing drowsiness and lowering the body’s temperature a little in preparation for sleeping through the night. MelatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels are high throughout the night, but as the sun comes back up, they drop, corresponding with increased wakefulness.

Are melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels altered in HD?

Since Huntington’s disease patients have problems regulating the normal sleeping/waking cycle, a group of researchers in the UK led by Prof Tom Warner wanted to ask whether the rise and fall of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels in HD patients is abnormal compared to unaffected individuals. Previous studies had measured patients’ melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep at a single time point, early in the morning, but Warner’s group wanted to monitor melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels throughout the 24-hour cycle to get a better sense of how the rhythm of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep production is affected in HD.

They recruited 13 patients with moderate to advanced HD, and 15 people who do not have the HD gene. They also included 14 people who carry the HD gene, but had not yet shown disease symptoms. Each person involved in the study spent a day and night in a private room, under supervision by clinicians. They could walk around and do what they liked during the day, but they weren’t allowed to nap, and the lights were out between 10 pm and 6 am. The researchers inserted an IV line so that they could collect a small amount of blood every hour, even in the middle of the night, with minimal interruption of the volunteers’ sleep.

MelatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep in HD and gene carriers: lower levels and improper timing

Using a sensitive type of chemical analysis, the researchers determined the amount of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep in each person’s blood, then compared the three groups with one another using a variety of statistical methods.

They found that the HD patients had much lower levels of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep in their blood than those without HD – around 85% lower on average. Presymptomatic carriers of the HD gene also had slightly lower melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels than normal.

Another finding was that HD patients and gene carriers showed more variation in the time of day that their melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels began to rise. Most of the volunteers without HD had a surge of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep around bedtime, while HD-affected individuals’ melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels rose at different times – some in the afternoon, some in the middle of the night.

An explanation for disrupted sleep in HD?

By consistently monitoring blood levels of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep for a full 24 hours in Huntington’s disease patients, presymptomatic HD carriers, and unaffected control participants, this study showed that melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels are indeed altered in HD, a finding which may help to explain why patients experience disrupted sleep.

The researchers go on to suggest that a low or poorly-timed surge of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep from the pineal glandpineal a gland in the brain that produces the hormone melatonin could mean that there’s something wrong with the timekeeper neuronsneuron Brain cells that store and transmit information in the SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms. Several different types of Huntington’s disease mice have shown problems in sleep and other cyclic behaviors controlled by the SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms. Abnormalities in signalling chemicals produced by the SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms have been found in HD brains, both human and mouse.

Back in 2011, we reported on a study in which melatonin treatment improved behavior and survival in Huntington’s disease mice. It’s not yet clear whether we can link that finding with the new discovery of decreased melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels in HD patients. But sleep disruption can be a major source of stress and can worsen the symptoms of many diseases. Improving sleep through melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep therapy, could be a positive change for the body and brain. However, it’s not yet clear whether melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep is effective in HD to improve sleep, let alone as a means of slowing down the progression of the disease.

A case for clinical trials of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep

There hasn’t been a clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep as a therapy for Huntington’s disease patients with sleep disturbances, but this study provides good evidence of HD-related changes in melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep levels, and suggests that a clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings might be warranted. MelatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep is already an approved supplement that many people buy over-the-counter or get on prescription, to adjust their sleep patterns. Some patients appear more responsive than others to melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep and other sleep aids; perhaps this could be explained by the variable timing of melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep production that this study found in HD patients.

Finally, these results don’t provide any explanation for why changes in melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep occur in HD. We can speculate that the SCNsuprachiasmatic nucleus the part of the brain that controls daily or 'circadian' rhythms or its communication with the pineal glandpineal a gland in the brain that produces the hormone melatonin may be disrupted, but the reasons for that are unclear. It’s also fairly clear that changes in melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep are only one of several things that can cause sleep disruption in Huntington’s disease, and we’re definitely not saying that every HD patient should take melatoninMelatonin a hormone produced by the pineal gland, important for regulating sleep. However, these results make a solid case for a clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings, and importantly, the study provides one explanation for why it’s so tough for many HD patients to catch some much-needed zzzs.

Learn more

• Original research paper: ‘Plasma melatonin is reduced in Huntington’s disease’ (full article requires payment or subscription)
• HDBuzz article on sleep disturbances in Huntington’s disease
• HDBuzz article on melatonin in HD mice