The circadian clock plays an unexpected role in neurodegenerative diseases

Although your body may deplore the many unpleasant effects of jet lag, your brain can thank you for traveling in many areas.

In a new study, researchers at Northwestern University induced jet lag in a Huntington's disease fruit fly model and found that this shift protected neurons from flies. The team then identified and tested a gene controlled by a circadian clock that, once reversed, also protected the brain from the disease.

The results reveal new potential treatment pathways to slow progression or prevent neurodegenerative diseases.

"It sounds counterintuitive, but we've shown that a little stress is good," said Dr. Ravi Allada of Northwestern, an expert in circadian rhythms who led the research. "We have subtly manipulated the circadian clock, and this stress seems to be neuroprotective."

The study will be published April 2 in the journal Cell reports. Allada is Distinguished Professor Edward C. Stuntz and Director of the Department of Neurobiology at Northwestern Weinberg College of Arts and Sciences.

Patients with neurodegenerative diseases often experience profound disturbances in their circadian rhythms or sleep-wake cycles. They may sleep more than usual or lose their ability to stay asleep. This can lead to night wandering, increased restlessness, general stress and decreased quality of life.

"We have known for a long time that a disturbed clock is an early indicator of a neurodegenerative disease," said Allada. "In many cases, sleep disturbance precedes any other symptom, but we did not know whether disruption of the circadian rhythm was a cause of the disease or a consequence of the disease."

To explore this question, Allada used the Huntington's disease fruit fly model, a model organism well-studied for circadian rhythms and neurodegenerative diseases. Although fruit flies may look completely different from humans, the neurons that govern the sleep-wake cycles of flies are remarkably similar to those of humans. Fruit flies bearing the mutant Huntington gene also exhibit human-like symptoms: reduced life span, motor deficits, neurodegeneration, circadian rhythm disturbances, and sick protein accumulation in the brain, which 'Aggregate and cause death of neurons.

"Normally, fruit flies wake up, become very active, then fall asleep and become inactive," Allada explained. "It's a 24-hour model." In the Huntington model, there's no rhythm, the flies wake up and fall asleep all the time. "

The Allada team has changed the circadian rhythms of flies in two different ways. For a group of flies, the researchers altered the environment of the latter by changing the daily synchronization of the day-night cycles. This manipulation led the flies to live a day of 20 hours instead of 24 hours. And for another group of flies, the researchers mutated a well-known gene to control the internal circadian clock.

"We basically gave the flies a jet lag every day of their lives," said Allada. "It's like traveling four hours east every day."

In both cases, the mutant proteins of Huntington's disease aggregated fewer and fewer dead neurons. Allada, who was expecting jet lag to inflict even more damage on the brain, was surprised. "We wondered if the clock had played a role in the disease," he said. "It turned out that the clock was important, but in a way that we had not predicted.

Allada and her team were so fascinated by the result that they pushed further the study. They decided to screen dozens of clock-controlled genes to identify one that could also protect the brain from neurodegenerative diseases.

The team is focused on a gene that codes for "protein organizing heat shock" or "hop" for short. Not only is hops controlled by the body's circadian clock, but the gene is also responsible for protein folding. Since misfolded proteins can lead to many neurodegenerative diseases, Allada has identified hops as an attractive target. He and his team destroyed the hops gene in flies with the protein that causes Huntington's disease and, again, were surprised. The removal of the gene restored the circadian clocks of flies, reduced the aggregation of diseased proteins in the brain and reduced the number of neurons killed by these proteins.

"We thought that inhibiting this gene that helps your proteins to fold back properly would make the situation worse, but they have improved," Allada said. "It shows again that a little stress is probably good."

Allada then plans to test this method in a fruit fly model of Alzheimer's disease. He believes that targeting and killing the hops gene could be an early intervention to slow the progression of various neurodegenerative diseases.