Gene linked to circadian rhythm identified

Discovery in Drosophila may provide clues to neurodegenerative diseases in humans

By Jim Fessenden

UMass Medical School Communications

May 21, 2013

Scientists at the UMass Medical School have identified a novel gene that calibrates circadian rhythms in the experimental model organism Drosophila. Responsible for encoding an RNA-binding protein, the Ataxin-2 gene has been linked to a number of neurodegenerative disorders in humans including spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease. These findings may prove important to understanding how the circadian clock governs eating and sleeping patterns in humans and how mutations in the Ataxin-2 gene contribute to neurodegenerative diseases. The study appears in the journal Science.

Circadian rhythms have a profound impact on animal behavior and physiology. They help determine at what time an animal feeds and sleeps, for example.

“What is so remarkable about the circadian clock is that even in the absence of environmental clues, such as daylight, it has the ability to continue functioning in 24-hour cycles. This allows us to sleep and wake at approximately the same time every day,” said Patrick Emery, PhD, associate professor of neurobiology and lead author of the study.

However, there is still much to be learned about the molecular mechanisms generating circadian rhythms and the neural circuits driving behavioral rhythms. Dr. Emery and colleagues found that the Ataxin-2 protein, which has been shown in previous studies to inhibit the production of certain proteins, plays a crucial role in the control of the circadian sleep/wake cycle. When Emery reduced expression of the Ataxin-2 gene in Drosophila, the flies were active two and half hours longer than on the previous day. Indeed, their circadian clock cycled with a period of 26.5 hours compared to the normal 24-hour cycle.

It turns out that Ataxin-2 regulates the expression of the circadian protein called “Period” in Drosophila. The concentration of Period protein determines the pace and phase of all circadian rhythms by oscillating between day and night. Ataxin-2 interacts with a previously characterized translation factor called “Twenty-Four” to increase Period concentration. This accounts for the increase to the circadian clock cycle.

“This was unexpected,” said Emery. “We thought Ataxin-2 would be a repressor of a circadian gene, but it turns out it works as an activator of Period translation. This suggests that Ataxin-2 can function either as an activator or as a repressor, depending on the mRNAs it targets and the proteins with which it associates.”

These findings may help explain how mutations in the Ataxin-2 gene contribute to neurodegenerative diseases. For instance, patients suffering from a form of the neurodegenerative disease spinocerebellar ataxia caused by Ataxin-2 mutations also experience REM sleep disruptions. “The circadian clock is well conserved betweenDrosophila and humans,” said Emery. “It will be important to determine whether Ataxin-2 also impacts circadian sleep/wake cycles in humans, and whether this contributes to sleep symptoms in patients.”