Overlooked 'housekeeping' gene plays unexpected role in seizures

August 26, 2020

Within cells, molecules known as transfer RNAs, or "tRNAs," play an important but unglamorous workhorse role in keeping the genetic translation process moving along from codes of DNA to functional proteins.

Because they play such a vital role in this translational "housekeeping," tRNAs are plentiful. There are hundreds of tRNA genes in mammalian cells and more than enough backup copies, just in case anything goes wrong. Yet because there are so many tRNAs, they've been largely overlooked in the search for the roots of disease processes.

University of California San Diego scientists studying tRNAs in mice have now found that a mutation in a tRNA gene called n-Tr20--expressed only in the brain--can disrupt the landscape of the entire cell, leading to a chain reaction altering brain function and behavior.

The new research is described August 26 in the journal Neuron.

Study first author Mridu Kapur, a postdoctoral scholar working in Professor Susan Ackerman's laboratory, says she and her colleagues found that n-Tr20 plays a role in the delicate balance of excitatory and inhibitory neurotransmission in the brain. A disruption in this balance has been implicated in numerous neurological diseases, including epilepsies and autism spectrum disorders.

"tRNAs have generally been overlooked in the hunt for the genetic causes of disease, but recent whole-genome sequencing projects have revealed that there are many variations in tRNA sequences in the human population," said Kapur. "Our study suggests the enormous potential for tRNA variants to contribute to disease outcomes and phenotypic variability."

The researchers found that a loss of n-Tr20, one of the members of a five-gene tRNA family, made mice resistant to seizures. While they note that their initial interest in this area came from the idea that a tRNA mutation could subsequently influence other gene mutations, their results not only confirm their speculations that tRNA mutations can influence other mutations, but indicate that these mutations alone can also alter brain function.

"You can imagine it's like a seesaw--if you push either way you can have problems," said Ackerman, a member of the Section of Neurobiology, Department of Cellular and Molecular Medicine and investigator at the Howard Hughes Medical Institute. "Keeping balance of these two opposing forces is essential for normal function. Shifting one way or another can lead to neurological diseases. It's becoming well accepted in the autism spectrum disorder field that what we are really seeing is an imbalance of excitatory/inhibitory neurotransmission."

Ackerman says part of the reason tRNAs have been overlooked in disease investigations is because researchers commonly concentrate on mutations in unique genes. A member of a large family such as n-Tr20 typically gets tossed in the genetic garbage can because they are too similar to one other.

"We never knew a mutation in a multi-copy tRNA gene could do anything like this," said Ackerman. "These findings make you think about people who have diseases with variable symptoms and how much this class of overlooked genes could be playing a role in their disease. So we're seeing this go from a behavior, such as seizure, all the way to the molecular underpinnings causing them."

The researchers say the results are likely the tip of the iceberg and are now turning their attention to studying tRNA links to disease in tissues outside the brain.
-end-
Coauthors of the Neuron paper include Archan Ganguly, Gabor Nagy, Scott Adamson, Jeffrey Chuang and Wayne Frankel.

University of California - San Diego

Related Brain Articles from Brightsurf:

Glioblastoma nanomedicine crosses into brain in mice, eradicates recurring brain cancer
A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier in mice could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.

Children with asymptomatic brain bleeds as newborns show normal brain development at age 2
A study by UNC researchers finds that neurodevelopmental scores and gray matter volumes at age two years did not differ between children who had MRI-confirmed asymptomatic subdural hemorrhages when they were neonates, compared to children with no history of subdural hemorrhage.

New model of human brain 'conversations' could inform research on brain disease, cognition
A team of Indiana University neuroscientists has built a new model of human brain networks that sheds light on how the brain functions.

Human brain size gene triggers bigger brain in monkeys
Dresden and Japanese researchers show that a human-specific gene causes a larger neocortex in the common marmoset, a non-human primate.

Unique insight into development of the human brain: Model of the early embryonic brain
Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain.

An optical brain-to-brain interface supports information exchange for locomotion control
Chinese researchers established an optical BtBI that supports rapid information transmission for precise locomotion control, thus providing a proof-of-principle demonstration of fast BtBI for real-time behavioral control.

Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.

Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.

Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.

Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.

Read More: Brain News and Brain Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.