The Link Between Sleep and Neurodegeneration

An important biological mechanism that is thought to protect brain cells from neurodegenerative diseases may also be involved in regulating sleep, according to a University of Pennsylvania study that was published yesterday. The research team found that a signaling pathway that helps prevent the buildup of abnormal protein aggregates in brain cells is also required for sleep in both fruit flies and zebrafish.

There have long been hints that sleep loss and sleep disorders are connected to neurodegenerative diseases, and the findings, published online today in Current Biology, reveal one possible explanation for the link. The results could potentially lead to new strategies against both sleep disorders and neurodegenerative diseases.

“Sleep fragmentation, which is characterized by repetitive short sleep interruptions, is one of the most common triggers of excessive daytime tiredness, especially in older people,” says senior author Nirinjini Naidoo. “Now that we know a major pathway that is involved in sleep regulation, we can target it to potentially improve fragmented sleep.”

How the processes underlying neurodegenerative disease might be connected to sleep disturbances has never been clear. But one hint comes from findings in lab animals that the brain during sleep dials up proteostasis processes that clear away abnormal and potentially harmful protein aggregates, such as those that clutter the brain in neurodegenerative disorders.

In the new study, the researchers scrutinized an important proteostasis process called the PERK signaling pathway, which, in response to a buildup of unwanted protein aggregates, causes cells temporarily to stop their assembly of most proteins. They found that when they suppressed PERK signaling in fruit flies or in the evolutionarily distant zebrafish, using small-molecule compounds that block a key component of the pathway, both sets of animals slept much less than normal. Blocking PERK with genetic techniques in flies brought similar results, while doing the reverse—forcing the overproduction of PERK—made the flies sleep more.

The team examined tiny groups of neurons that produce a key wakefulness-promoting hormone in flies. They found that knocking down PERK in these neurons at night was enough to make the flies sleep less, whereas overproducing PERK made them sleep more. In one subset of these neurons, the researchers were able to verify that boosting or reducing PERK had the effect of suppressing or unleashing production of the wakefulness hormone.

“This raises the possibility that PERK regulation of sleep occurs within multiple brain circuits,” says first author Sarah Ly.