There's plenty to be said about the negative health effects of jet lag, but could a journey through the clouds have a silver lining? New research out of Northwestern University suggests that indeed it might, uncovering evidence that disruptions to circadian clocks can have a protective effect on neurons, opening up some interesting new pathways for research into degenerative brain diseases.
"We have long known that a disrupted clock is an early indicator of neurodegenerative disease," says Northwestern's Dr. Ravi Allada, who led the research. "In many cases, sleep disruption precedes any other symptom. But we didn't know whether the circadian disruption is a cause of the disease or a consequence of the disease."
In search of answers to this mystery, the researchers turned to a trusted model for studying both circadian rhythms and brain disease, the humble fruit fly. Though there are obvious differences between these insects and humans, there are also some important similarities that serve as useful tools for scientists in the field.
This is particularly true of those with Huntington's disease, as fruit flies engineered to possess the mutant gene responsible for the disease exhibit a lot of the same symptoms as human patients, including reduced lifespan, impaired motor abilities and the buildup of diseased proteins in the brain that kill off neurons. And critically, the neurons that regulate their sleep and wake cycles are very similar to those of humans.
For their experiments, the researchers interfered with the circadian rhythms of the insects in a couple of ways. For one group, they simply altered their environments to shake up their exposure to light and darkness, tricking them into living a 20-hour day rather than a 24-hour day. For a second group, they mutated a gene that is known to control their internal circadian clock.
"We essentially gave the flies jet lag for every day of their lives," Allada says. "It's like traveling four hours east every day."
Both groups of flies exhibited a lower buildup of Huntington's disease proteins and, therefore, less of their neurons died. To better understand the mechanics behind these peculiar results, and how they might one day be leveraged for better medical outcomes, the researchers screened dozens of genes that the circadian clock regulates in the hopes of finding one that related to the degeneration of the brain.
This led them to a gene that codes for what is known as the heat shock organizing protein, or "hop" for short. This particular protein is responsible for protein folding, which in turn can lead to a range of brain diseases through misfolded proteins, so the researchers were interested to see what happened when they switched the gene off. Sure enough, it returned their circadian clocks to normal, lowered the buildup of diseased proteins and therefore reduced the amount of neurons killed.
"It seems counterintuitive, but we showed that a little bit of stress is good," says Allada. "We subtly manipulated the circadian clock, and that stress appears to be neuroprotective."
From here, Allada and his team want to test out the same technique on a fruit fly model of Alzheimer's disease. They are hopeful that with further research, knocking out the hop gene could prove to be an effective way of putting the brakes on a range of brain diseases.
The research has been published in the journal Cell Reports.
Source: Northwestern University
