Overlooked 'housekeeping' gene plays unexpected role in seizures

Date:
August 26, 2020
Source:
University of California - San Diego
Summary:
Molecules known as tRNAs are often overlooked in studies of disease
processes. Researchers have found that a mutation in a tRNA gene
called n-Tr20 -- expressed only in the brain -- can disrupt the
landscape of entire cells, leading to chain reactions that alter
brain function and behavior.



FULL STORY ========================================================================== 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 conditions, 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.

Coauthors of the Neuron paper include Archan Ganguly, Gabor Nagy, Scott Adamson, Jeffrey Chuang and Wayne Frankel.

The research was supported by the National Institutes of Health (R01
NS094637 and R37 NS031349) and the Howard Hughes Medical Institute. Amino
acid metabolomics was supported by Mass Spectrometry Core of the Salk
Institute (NIH-NCI CCSG P30 014195) and the Helmsley Center for Genomic Medicine.


========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Mario
Aguilera. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mridu Kapur, Archan Ganguly, Gabor Nagy, Scott I. Adamson,
Jeffrey H.

Chuang, Wayne N. Frankel, Susan L. Ackerman. Expression of the
Neuronal tRNA n-Tr20 Regulates Synaptic Transmission and Seizure
Susceptibility.

Neuron, 2020; DOI: 10.1016/j.neuron.2020.07.023 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200826141412.htm

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