Sleep Pathway May Be Linked to Neurodegenerative Diseases, Study Shows

An important signaling pathway that helps protect brain cells from neurodegenerative diseases such as Parkinson’s disease is also required for sleep in fruit flies and zebrafish, according to a study.

The findings support a link between sleep loss and neurodegenerative diseases. As this mechanism was found in two distantly related species, it may exist in humans, which would support new strategies to treat both sleeping disorders and neurodegenerative diseases.

The study, “Evolutionarily Conserved Regulation of Sleep by the Protein Translational Regulator PERK,” was published in the journal Current Biology. 

Studies have suggested that sleep disturbances are a common feature of neurodegenerative diseases such as Parkinson’s.

While the link between sleep and neurodegenerative diseases is unclear, there is evidence in mice that during sleep, the brain ramps up the process known as proteostasis — the clearing of potentially harmful clumps of protein that clutter the brain. 

Clumps of the protein alpha-synuclein in brain cells is a hallmark of Parkinson’s disease. 

“A possible function of sleep could be to regulate proteostasis in the brain, which could explain its link to neurological health,” the researchers wrote. 

Cellular proteostasis is the proper coordination of protein production and distribution, and when disrupted by the clumping of proteins, a process known as unfolded protein response (UPR) becomes activated. This slows protein production allowing for the clearance of protein clumps, restoring proteostasis and preventing cell death. 

However, the connection between UPR activation and sleep remains unknown. 

Researchers at the University of Pennsylvania, in collaboration with investigators at the California Institute of Technology, studied the role of a pathway controlled by the enzyme PKR-like ER kinase (PERK) that mediates UPR activation.

As the UPR system is common in many species, the scientists used fruit flies as an example of invertebrates, and zebrafish to represent vertebrate species. 

Sleep deprivation leads to PERK pathway activation across several species. Researchers wanted to understand whether the activation of this pathway was specific to sleep deprivation or whether PERK pathway activation could occur over the course of normal wakefulness.

They tested a marker for PERK activation in fruit flies at the beginning of the day and at the end of the day. The marker was found to be elevated at the end of the day, demonstrating that PERK pathway activation was linked to wakefulness. 

When scientists suppressed the PERK pathway in fruit flies using a selective inhibitor of PERK (GSK2606414), sleep was lowered by 31%. The inhibitor treatment reduced zebrafish sleep by 27% at night. 

The researchers used a genetic approach to lower the production of PERK in neurons of the fruit flies. These flies slept significantly less during both the day and at night, with decreases in the number and length of sleeping bouts. 

In contrast, overproduction of PERK by around 14-fold led to a significant increase in sleep during both the day and night, due to increases in sleep bouts and sleep length. 

To explore the underlying mechanisms connecting PERK activity to sleep, the researchers examined a special group of neurons that produce a wakefulness-promoting small protein called pigment dispersing factor (PDF), which is elevated during the day and lowered at night. 

The lower production of PERK in PDF neurons significantly lowered sleep in fruit flies, and was accompanied by a significant increase in PDF expression at night, when levels are normally low. When PERK levels were increased, sleep was significantly extended and PDF expression was significantly lower during the day when it is normally high. 

“Taken together, these results demonstrate that protein synthesis pathways like PERK could represent a general mechanism of sleep and wake regulation and provide greater insight into the relationship between sleep and proteostasis,” the researchers wrote.

“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,” study author Nirinjini Naidoo, PhD, said in a press release. “Now that we know a major pathway that is involved in sleep regulation, we can target it to potentially improve fragmented sleep.”

“Our findings suggest that one of the conserved functions of sleep may be to mitigate cellular stress caused by wakefulness,” Naidoo said.