Discovery could lead to
targets for new therapies
August 19, 2019
NIH/National Institute on
Deafness and Other Communication Disorders
Researchers believe that
stuttering -- a potentially lifelong and debilitating speech disorder -- stems
from problems with the circuits in the brain that control speech, but precisely
how and where these problems occur is unknown. Using a mouse model of
stuttering, scientists report that a loss of cells in the brain called
astrocytes are associated with stuttering. The mice had been engineered with a
human gene mutation previously linked to stuttering. The study offers insights
into the neurological deficits associated with stuttering.
Researchers believe that
stuttering -- a potentially lifelong and debilitating speech disorder -- stems
from problems with the circuits in the brain that control speech, but precisely
how and where these problems occur is unknown. Using a mouse model of
stuttering, scientists report that a loss of cells in the brain called
astrocytes are associated with stuttering. The mice had been engineered with a
human gene mutation previously linked to stuttering. The study, which appeared
online in the Proceedings of the National Academy of Sciences, offers
insights into the neurological deficits associated with stuttering.
The loss of astrocytes, a
supporting cell in the brain, was most prominent in the corpus callosum, a part
of the brain that bridges the two hemispheres. Previous imaging studies have
identified differences in the brains of people who stutter compared to those
who do not. Furthermore, some of these studies in people have revealed
structural and functional problems in the same brain region as the new mouse
study.
The study was led by Dennis
Drayna, Ph.D., of the Section on Genetics of Communication Disorders, at the
National Institute on Deafness and Other Communication Disorders (NIDCD), part
of the National Institutes of Health. Researchers at the Washington University
School of Medicine in St. Louis and from NIH's National Institute of Biomedical
Imaging and Bioengineering, and National Institute of Mental Health
collaborated on the research.
"The identification of
genetic, molecular, and cellular changes that underlie stuttering has led us to
understand persistent stuttering as a brain disorder," said Andrew
Griffith, M.D., Ph.D., NIDCD scientific director. "Perhaps even more
importantly, pinpointing the brain region and cells that are involved opens
opportunities for novel interventions for stuttering -- and possibly other
speech disorders."
Stuttering is characterized by
pauses and repeated or prolonged sounds, syllables or words, which disrupt the
normal flow of speech. People who stutter know what they want to say, but they
have trouble saying it. The condition is most commonly seen in young children
who typically outgrow the problem. However, for 1 in 4 children who experience
early stuttering, the condition persists as a lifelong communication problem.
It is estimated that as many as 1% of adults in the United States are affected
by stuttering.
"The brain imaging
studies of people who stutter are important, but those results can only take us
so far," said Drayna. One challenge, he said, is that the imaging studies
cannot decipher if the differences contribute to stuttering or are an effect of
stuttering.
"By taking a genetic
approach, we have been able to begin deciphering the neuropathology of
stuttering, first at the molecular level by identifying genetic mutations, and
now at the cellular level," added Drayna.
Earlier research by Drayna and
colleagues has identified several genes associated with stuttering. In this
study, the researchers set out to identify changes in the brain brought on by
the mutations in a gene called GNPTAB, one of the genes previously linked to
stuttering. The scientists engineered this human stuttering mutation into the
mice to create a mouse model. The mice with the GNPTAB mutation had long pauses
in their stream of vocalizations, similar to those found in people with the
same mutation. Like people who stutter, the mice were normal in all other ways,
reinforcing earlier research that suggests that the mice can serve as a valid
animal model for important features of this disorder.
The investigators next
examined brain tissue from the mice and found a decrease in astrocytes, but not
other cell types, in the animals with the genetic mutation compared to the mice
without the mutation. Astrocytes play a critical role in supporting nerve cells
by carrying out a wide range of functions, such as supplying nerve cells with oxygen
and nutrients and providing structural support.
The loss of astrocytes was
more pronounced in the corpus callosum of the mutant mice. In addition, using
advanced magnetic resonance imaging (MRI) methods, the researchers detected
reduced local volume of the corpus callosum in the mutant mice despite normal
diffusion tensor MRI values, providing further support for a defect in this
brain region.
Containing as many as 200
million nerve fibers, the corpus callosum enables communication between the
brain's left and right hemispheres, helping to integrate signals for processes
that involve both hemispheres, such as physical coordination and use of
language.
Follow-up experiments in which
the GNPTAB human stuttering mutation was introduced into individual brain cell
types -- rather than the entire mouse -- confirmed that the vocalization defect
is specific to astrocytes. The mice did not have the stuttering-like
vocalizations when the mutation was engineered into other types of brain cells.
All of the stuttering genes
that have been identified over the past decade are involved in intracellular
trafficking, the process that cells use to move proteins and other components
to their correct locations within the cell. Defects in cellular trafficking
have been linked to other neurological disorders, such as amyotrophic lateral
sclerosis (ALS), Parkinson's disease, and Alzheimer's disease, suggesting that
certain nerve cell pathways are particularly sensitive to impairment of this
process. The research does not indicate, however, that persistent stuttering is
an early indicator of these other disorders.
If future research confirms
that stuttering in people with GNPTAB mutations derives from a loss of
astrocytes in the brain, these findings could open the door to new therapeutic
strategies for some people with persistent developmental stuttering by
targeting associated molecular pathways and cells.
Story Source:
Materials provided by NIH/National Institute on
Deafness and Other Communication Disorders. Note: Content may be
edited for style and length.
Journal Reference:
Tae-Un Han, Jessica Root,
Laura D. Reyes, Elizabeth B. Huchinson, Johann du Hoffmann, Wang-Sik Lee, Terra
D. Barnes, Dennis Drayna. Human GNPTAB stuttering mutations engineered
into mice cause vocalization deficits and astrocyte pathology in the corpus
callosum. Proceedings of the National Academy of Sciences, 2019; 201901480
DOI: 10.1073/pnas.1901480116
No comments:
Post a Comment