Circadian clock unusual effect on neurodegenerative diseases

Disrupted sleep patterns may protect the health of the brain, according to a new study published in the journal Cell Reports.

Researchers from Northwestern University in Evanston, Illinois induced jet lag in fruit flies modeled to have Huntington disease. Thy found that jet lag seemingly protected the flies’ neurons. Then, identified and tested a circadian clock-controlled gene that, when knocked down, also protected the brain from the disease.

Fruit flies have neurons to govern wake cycles that are strikingly similar to humans, and flies with the mutant Huntington gene demonstrate symptoms similar to humans with the disease, according to researchers. The research team altered the flies' circadian rhythms in two different ways. For one group of flies, the researchers altered the flies' environment by changing the daily timing of light-dark cycles. This manipulation caused the flies to live a 20-hour day instead of a 24-hour day. For another group of flies, the researchers mutated a gene that is well-known for controlling the internal circadian clock.

In both cases, the mutant Huntington disease proteins aggregated less and fewer neurons died.

From there, the researchers decided to screen through dozens of clock-controlled genes to pinpoint one that also might similarly protect the brain against neurodegenerative diseases. The team zeroed in on a gene that encodes the heat shock organizing protein (Hop). Not only is Hop controlled by the body's circadian clock, the gene is also responsible for protein folding, researchers said. Misfolded proteins can result in many different neurodegenerative diseases, so the research team knocked down the Hop gene in flies with the protein that causes Huntington disease. Knocking down the gene restored the flies' arrhythmic circadian clocks, reduced the aggregation of diseased proteins in the brain, and reduced the number of neurons killed by those proteins.

The findings reveal potential new treatment pathways to slow the progression of or prevent neurodegenerative diseases, according to Ravi Allada, MD, professor and chair of the department of neurobiology at Northwestern University, and lead author of the study.

"It seems counterintuitive, but we showed that a little bit of stress is good," said Allada in a press statement. "We subtly manipulated the circadian clock, and that stress appears to be neuroprotective."

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

"We have long known that a disrupted clock is an early indicator of neurodegenerative disease," said Allada. "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."

Allada said he plans to test this method in a fruit fly model of Alzheimer's disease. He believes that targeting and knocking down the Hop gene could potentially be an early intervention for slowing the progression of various neurodegenerative diseases.

"We thought that inhibiting this gene that helps your proteins fold properly would make things worse, but they got better," Allada said. "It again shows that a little bit of stress is probably good."