neurodegenerative diseases

Circadian clock plays unexpected role in neurodegenerative diseases

Seemingly counterintuitive evidence shows that disrupted sleep protects the brain

April 2, 2019

Science Daily/Northwestern University

Researchers induced jet lag in a fruit fly model of Huntington disease and found that jet lag protected the flies' neurons.

 

While your body might bemoan the many uncomfortable effects of jet lag, your brain may be thanking you for that cross-time zone travel.

 

In a new study, Northwestern University researchers induced jet lag in a fruit fly model of Huntington disease and found that jet lag protected the flies' neurons. The team then identified and tested a circadian clock-controlled gene that, when knocked down, also protected the brain from the disease.

 

The findings reveal potential new treatment pathways to slow the progression of or prevent neurodegenerative diseases.

 

"It seems counterintuitive, but we showed that a little bit of stress is good," said Northwestern's Dr. Ravi Allada, a circadian rhythms expert who led the research. "We subtly manipulated the circadian clock, and that stress appears to be neuroprotective."

 

The study will be published April 2 in the journal Cell Reports. Allada is the Edward C. Stuntz Distinguished Professor and chair of the department of neurobiology in Northwestern's Weinberg College of Arts and Sciences.

 

Patients with neurodegenerative diseases often experience profound disruptions in their circadian rhythms, or sleep-wake cycles. 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," Allada said. "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."

 

To probe this question, Allada employed the fruit fly model of Huntington disease, a well-studied model organism for both circadian rhythms and neurodegenerative diseases. Although fruit flies might seem completely different from humans, the neurons that govern flies' sleep-wake cycles are strikingly similar to humans'. Fruit flies that have the mutant Huntington gene also demonstrate similar symptoms as humans with the disease: reduced lifespan, motor deficits, neurodegeneration, disrupted circadian rhythms and an accumulation of diseased proteins in the brain, which aggregate and cause neurons to die.

 

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

 

Allada's team altered the flies' circadian rhythms 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. And for another group of flies, the researchers mutated a gene that is well known for controlling the internal circadian clock.

 

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

 

In both cases, the mutant Huntington disease proteins aggregated less and fewer neurons died. Allada, who expected jet lag to inflict even more damage on the brain, was surprised. "We had wondered if the clock played a role in the disease," he said. "It turned out that the clock was important -- but in a manner that we did not predict."

 

Allada and his team were so fascinated by the result that they took the study one step further. They 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," or "hop" for short. Not only is hop controlled by the body's circadian clock, the gene is also responsible for protein folding. Because misfolded proteins can result in many different neurodegenerative diseases, Allada thought hop made an interesting target. He and his team knocked down the hop gene in flies with the protein that causes Huntington disease and -- again -- were surprised. 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.

 

"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."

 

Next, Allada 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.

https://www.sciencedaily.com/releases/2019/04/190402113220.htm

Native California medicinal plant may hold promise for treating Alzheimer's

Salk scientists identify possible healing compound in Yerba santa

February 20, 2019

Science Daily/Salk Institute

The medicinal powers of aspirin, digitalis, and the anti-malarial artemisinin all come from plants. A discovery of a potent neuroprotective and anti-inflammatory chemical in a native California shrub may lead to a treatment for Alzheimer's disease based on a compound found in nature.

 

"Alzheimer's disease is a leading cause of death in the United States," says Senior Staff Scientist Pamela Maher, a member of Salk's Cellular Neurobiology Laboratory, run by Professor David Schubert. "And because age is a major risk factor, researchers are looking at ways to counter aging's effects on the brain. Our identification of sterubin as a potent neuroprotective component of a native California plant called Yerba santa (Eriodictyon californicum) is a promising step in that direction."

 

Native California tribes, which dubbed the plant "holy herb" in Spanish, have long used Yerba santa for its medicinal properties. Devotees brew its leaves to treat respiratory ailments, fever and headaches; and mash it into a poultice for wounds, sore muscles and rheumatism.

 

To identify natural compounds that might reverse neurological disease symptoms, Maher applied a screening technique used in drug discovery to a commercial library of 400 plant extracts with known pharmacological properties. The lab had previously used this approach to identify other chemicals (called flavonoids) from plants that have anti-inflammatory and neuroprotective properties.

 

Through the screen, the lab identified a molecule called sterubin as Yerba santa's most active component. The researchers tested sterubin and other plant extracts for their impact on energy depletion in mouse nerve cells, as well as other age-associated neurotoxicity and survival pathways directly related to the reduced energy metabolism, accumulation of misfolded, aggregated proteins and inflammation seen in Alzheimer's. Sterubin had a potent anti-inflammatory impact on brain cells known as microglia. It was also an effective iron remover -- potentially beneficial because iron can contribute to nerve cell damage in aging and neurodegenerative diseases. Overall, the compound was effective against multiple inducers of cell death in the nerve cells, according to Maher.

 

"This is a compound that was known but ignored," Maher says. "Not only did sterubin turn out to be much more active than the other flavonoids in Yerba santa in our assays, it appears as good as, if not better than, other flavonoids we have studied."

 

Next, the lab plans to test sterubin in an animal model of Alzheimer's, then determine its drug-like characteristics and toxicity levels in animals. With that data, Maher says, it might be possible to test the compound in humans, although it would be critical to use sterubin derived from plants grown under standardized, controlled conditions. She says the team will likely generate synthetic derivatives of sterubin.

https://www.sciencedaily.com/releases/2019/02/190220174105.htm

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