Timing is everything: Circadian rhythms, protein production and disease

Protein production by the clock: mouse over to learn more. (Illustration: Yana Payusova, used with permission.)

Second in a two-part series on circadian biology and disease. Read part 1.

We are oscillating beings. Life itself arose among the oscillations of the waves and the oscillations between darkness and light. The oscillations are carried in our heartbeats and in our circadian sleep patterns.

A new study in Cell shows how these oscillations reach all the way down into our cells and help mastermind the timing of protein production.

It’s a whole new layer of biology that could shed brand new light on our understanding of conditions such as cancer, autism and metabolic disorders, which may involve disrupted protein production. And it grew out of research on tuberous sclerosis complex (TSC), a rare genetic disorder that often causes autism.

Altered sleep, altered proteins?

Jonathan Lipton, MD, PhD, a sleep specialist in Boston Children’s Department of Neurology, was intrigued that children with TSC and other neurodevelopmental disorders—including 50 to 90 percent of children with autism—have significant sleep disturbances.

“These kids are waking up in the middle of the night for hours at a time,” says Lipton, who is also part of the Harvard Medical School Division of Sleep Medicine. “This completely disrupts families’ lives—and has motivated my work in the lab: Why is sleep disruption such a major part of these disorders?”

Research on a rare disease, TSC, led Sahin (L) and Lipton to new insights about circadian rhythms' relationship with disease in general.
Research on a rare disease, TSC, led Sahin (L) and Lipton to new insights about circadian rhythms’ relationship with disease in general.

He and Mustafa Sahin, MD, PhD, who does research on TSC at Boston Children’s FM Kirby Neurobiology Center, speculated that something is wrong with these children’s circadian rhythms. TSC’s underlying biology is fairly well understood, providing an opportunity to delve into this question.

Lipton and Sahin began by looking at the mTOR pathway, a fundamental cellular growth pathway that is over-activated in TSC. It regulates gene transcription, the first step in making proteins, and Sahin has shown that in TSC, over-activation of mTOR causes neurons to develop abnormally and form improper connections.

But is mTOR connected to circadian rhythms? In looking for a connection, Lipton and Sahin found that mTOR—through another protein called S6K1—regulates a protein called BMAL1 that is crucial for the expression of circadian rhythms. “It’s been known for about 15 years that without BMAL1, you can’t have circadian rhythms,” Lipton says.

Like two gears in a clockworks, the mTOR pathway cyclically activates BMAL1, which then helps activate the cellular protein-making machinery in the ribosomes, the researchers found. As a result, they observed peaks and troughs of when proteins are made during a 24-hour day.

Delegating control

brain circadian rhythmsThey further showed through their experiments that protein synthesis is turned on even when genes aren’t being transcribed. “A whole part of circadian oscillation is at the level of the protein synthesis machinery, and occurs independently of DNA transcription,” says Sahin. “It’s another leg of the stool.”

Why is this important? Protein synthesis is fundamental to pretty much everything our cells do hour to hour. The circadian system helps make sure the right proteins are made at the right time—for example, anticipating the liver enzymes you will need in the morning to digest your breakfast.

“The single most important thing to test is how this will play out in disease,” says Lipton, “particularly in disease in which protein synthesis is implicated.”

If the timing of protein synthesis is thrown off, it could lead to shortages of certain enzymes when they’re most needed, or cause accumulations of proteins that aren’t needed. Here are some disease scenarios Lipton is speculating about:

  • Neurodevelopmental disorders: Proteins are critical in signaling at synapses—the junctions between neurons. Too much or too little of a protein at a given time could disrupt brain function and contribute to conditions like autism. (Since sleep disruption is common in these disorders, a big question in the field is whether sleep disruption is a byproduct or a cause, says Lipton.)
  • Metabolic disease: The making of enzymes at specific times is key to our ability to break down food and other compounds. “Problems with protein oscillations may disrupt cells’ ability to dispose of metabolic byproducts,” says Lipton. “It can affect their ability to handle physiological toxicity—like missing a trash pickup.”
  • Neurodegenerative diseases: The researchers speculate that disorders such as Parkinson’s could result from a mismatch between the timing of protein synthesis and synthesis of enzymes to break the proteins down.
  • Cancer: Cancer cells are already known to have dysregulated protein synthesis. Perhaps altered circadian regulation adds to a cancer’s virulence by removing an important brake in the system.

Additionally, knowing when certain enzymes are made could inform the timing of drug therapy. Chronotherapeutics, a concept that began in the cancer world as an attempt to reduce the side effects of chemotherapy, takes advantage of these natural oscillations. (At Boston Children’s, it is starting to become a part of epilepsy treatment.)

Circadian rhythms are coming to be seen as a fundamental part of our biology, and circadian or sleep disturbances have been linked to obesity, diabetes, cardiovascular disease and even inflammation. Knowing how the circadian clock interacts with protein synthesis could provide a whole new angle on medicine.

 

Ed. note: Read an update on this research in Cell Reports.