GREATER RATES OF MITOCHONDRIAL MUTATIONS DISCOVERED IN CHILDREN BORN TO OLDER MOTHERS

The discovery of a "maternal age effect" by a team of Penn State scientists that could be used to predict the accumulation of mitochondrial DNA mutations in maternal egg cells -- and the transmission of these mutations to children -- could provide valuable insights for genetic counseling. These mutations cause more than 200 diseases and contribute to others such as diabetes, cancer, Parkinson's disease, and Alzheimer's disease. The study found greater rates of the mitochondrial DNA variants in children born to older mothers, as well as in the mothers themselves. The research will be published in the early online edition of theProceedings of the National Academy of Sciences on October 13, 2014.

 

Mitochondria are structures within cells that produce energy and that contain their own DNA. "Many mitochondrial diseases affect more than one system in the human body," said Kateryna Makova, professor of biology and one of the study's primary investigators. "They affect organs that require a lot of energy, including the heart, skeletal muscle, and brain. They are devastating diseases and there is no cure, so our findings about their transmission are very important."

The multidisciplinary research team set out to learn whether maternal age is important in the accumulation of mitochondrial DNA (mtDNA) mutations, both in the mother and in the child as a result of transmission. Collaborating with Ian Paul, a pediatrician at the Penn State Milton S. Hershey Medical Center, they took samples of blood and of cells inside the cheek from 39 healthy mother-child pairs. Because mtDNA is inherited only maternally, paternal mtDNA was not a factor in the study. Studying healthy individuals gave the researchers a baseline for future studies of disease-causing mutations.

Through DNA sequencing, they found more mutations in blood and cheek cells in the older mothers in the study. Maternal age of study participants ranged from 25 to 59. "This finding is not surprising," Makova said, "because as we age, cells keep dividing, and therefore we will have more mutant genes." But finding greater rates of mutations in children born to the older mothers did come as a surprise. The researchers believe a similar mutation process is occurring both in the cells of the mothers' bodies and in their germ lines.

The study led to another important discovery about egg-cell development. Although it was known that developing egg cells go through a "bottleneck" period that decreases the number of mtDNA molecules, scientists didn't know how small or large this bottleneck is. "If the bottleneck is large, the genetic makeup of the mother's mitochondria will be passed to her children," Makova explained. "However, if it is tiny -- if there is a severe decrease in mitochondrial molecules during the egg-cell development -- then the genetic makeup of the child might differ dramatically from that of the mother. What we discovered is that this bottleneck is indeed very small."

This finding is especially important for mothers who have a mitochondrial disease. For many mitochondrial diseases, 70 to 80 percent of molecules need to have the disease-causing variant for the disease to manifest itself. But for others, only 10 percent of the mtDNA molecules with the variant are needed to cause disease. "If the bottleneck is very small, as we've found in our study, these percentages can change dramatically," Makova said. "Knowing the size of the bottleneck allows us to predict, within a range, the percentage of disease-carrying molecules that will be passed on to the child."

Knowledge about both the maternal age effect and the bottleneck size is useful in family planning. "We have some predictive power now and can assist genetic counselors in advising couples about the chances of mitochondrial diseases being passed to the next generation," Makova said. "Everyone is concerned about Down syndrome because that is a common genetic problem. We have now added another set of genetic disorders that also might be affected by the age of the mother. It is good for couples to have this knowledge as they make family-planning decisions."

AREA OF BRAIN RESPONSIBLE FOR EXERCISE MOTIVATION DISCOVERED

Scientists at Seattle Children's Research Institute have discovered an area of the brain that could control a person's motivation to exercise and participate in other rewarding activities -- potentially leading to improved treatments for depression.

Dr. Eric Turner, a principal investigator in Seattle Children's Research Institute's Center for Integrative Brain Research, together with lead author Dr. Yun-Wei (Toni) Hsu, have discovered that a tiny region of the brain -- the dorsal medial habenula -- controls the desire to exercise in mice. The structure of the habenula is similar in humans and rodents and these basic functions in mood regulation and motivation are likely to be the same across species.

Exercise is one of the most effective non-pharmacological therapies for depression. Determining that such a specific area of the brain may be responsible for motivation to exercise could help researchers develop more targeted, effective treatments for depression.

"Changes in physical activity and the inability to enjoy rewarding or pleasurable experiences are two hallmarks of major depression," Turner said. "But the brain pathways responsible for exercise motivation have not been well understood. Now, we can seek ways to manipulate activity within this specific area of the brain without impacting the rest of the brain's activity."

Dr. Turner's study, titled "Role of the Dorsal Medial Habenula in the Regulation of Voluntary Activity, Motor Function, Hedonic State, and Primary Reinforcement," was published by the Journal of Neuroscience and funded by the National Institute of Mental Health and National Institute on Drug Abuse. The study used mouse models that were genetically engineered to block signals from the dorsal medial habenula. In the first part of the study, Dr. Turner's team collaborated with Dr. Horacio de la Iglesia, a professor in University of Washington's Department of Biology, to show that compared to typical mice, who love to run in their exercise wheels, the genetically engineered mice were lethargic and ran far less. Turner's genetically engineered mice also lost their preference for sweetened drinking water.

"Without a functioning dorsal medial habenula, the mice became couch potatoes," Turner said. "They were physically capable of running but appeared unmotivated to do it." In a second group of mice, Dr. Turner's team activated the dorsal medial habenula using optogenetics -- a precise laser technology developed in collaboration with the Allen Institute for Brain Science. The mice could "choose" to activate this area of the brain by turning one of two response wheels with their paws. The mice strongly preferred turning the wheel that stimulated the dorsal medial habenula, demonstrating that this area of the brain is tied to rewarding behavior.

Past studies have attributed many different functions to the habenula, but technology was not advanced enough to determine roles of the various subsections of this area of the brain, including the dorsal medial habenula.

"Traditional methods of stimulation could not isolate this part of the brain," Turner said. "But cutting-edge technology at Seattle Children's Research Institute makes discoveries like this possible."

As a professor in the University of Washington Department of Psychiatry and Behavioral Sciences, Dr. Turner treats depression and hopes this research will make a difference in the lives of future patients.

"Working in mental health can be frustrating," Turner said. "We have not made a lot of progress in developing new treatments. I hope the more we can learn about how the brain functions the more we can help people with all kinds of mental illness."

ON OFF SWITCH FOR AGING CELLS DISCOVERED BY SCIENTISTS

Scientists at the Salk Institute have discovered an on-and-off “switch” in cells that may hold the key to healthy aging. This switch points to a way to encourage healthy cells to keep dividing and generating, for example, new lung or liver tissue, even in old age.

In our bodies, newly divided cells constantly replenish lungs, skin, liver and other organs. However, most human cells cannot divide indefinitely–with each division, a cellular timekeeper at the ends of chromosomes shortens. When this timekeeper, called a telomere, becomes too short, cells can no longer divide, causing organs and tissues to degenerate, as often happens in old age. But there is a way around this countdown: some cells produce an enzyme called telomerase, which rebuilds telomeres and allows cells to divide indefinitely.

In a new study published September 19 in the journalGenes and Development, scientists at the Salk Institute have discovered that telomerase, even when present, can be turned off.

“Previous studies had suggested that once assembled, telomerase is available whenever it is needed,” says senior author Vicki Lundblad, professor and holder of Salk’s Ralph S. and Becky O'Connor Chair. “We were surprised to discover instead that telomerase has what is in essence an ‘off’ switch, whereby it disassembles.”

Understanding how this “off” switch can be manipulated–thereby slowing down the telomere shortening process–could lead to treatments for diseases of aging (for example, regenerating vital organs later in life).

Lundblad and first author and graduate student Timothy Tucey conducted their studies in the yeast Saccharomyces cerevisiae, the same yeast used to make wine and bread. Previously, Lundblad’s group used this simple single-celled organism to reveal numerous insights about telomerase and lay the groundwork for guiding similar findings in human cells.

“We wanted to be able to study each component of the telomerase complex but that turned out to not be a simple task,” Tucey said. Tucey developed a strategy that allowed him to observe each component during cell growth and division at very high resolution, leading to an unanticipated set of discoveries into how–and when–this telomere-dedicated machine puts itself together.

Every time a cell divides, its entire genome must be duplicated. While this duplication is going on, Tucey discovered that telomerase sits poised as a “preassembly” complex, missing a critical molecular subunit. But when the genome has been fully duplicated, the missing subunit joins its companions to form a complete, fully active telomerase complex, at which point telomerase can replenish the ends of eroding chromosomes and ensure robust cell division.

Surprisingly, however, Tucey and Lundblad showed that immediately after the full telomerase complex has been assembled, it rapidly disassembles to form an inactive “disassembly” complex — essentially flipping the switch into the “off” position. They speculate that this disassembly pathway may provide a means of keeping telomerase at exceptionally low levels inside the cell. Although eroding telomeres in normal cells can contribute to the aging process, cancer cells, in contrast, rely on elevated telomerase levels to ensure unregulated cell growth. The “off” switch discovered by Tucey and Lundblad may help keep telomerase activity below this threshold.