Unraveling the mystery of Gao, a protein implicated in movement
disorders
Scientists illuminate the protein's role in rare genetic diseases often diagnosed during infancy or childhood

Date:
February 3, 2021
Source:
Scripps Research Institute
Summary:
Scientists have clarified the workings of a mysterious protein
called Gao, which is one of the most abundant proteins in the
brain and, when mutated, causes severe movement disorders.



FULL STORY ========================================================================== Scientists at Scripps Research have clarified the workings of a mysterious protein called Gao, which is one of the most abundant proteins in the
brain and, when mutated, causes severe movement disorders.


==========================================================================
The findings, which appear in Cell Reports, are an advance in the
basic understanding of how the brain controls muscles and could lead to treatments for children born with Gao-mutation movement disorders. Such conditions - - known as GNAO1-related neurodevelopmental disorders --
were discovered only in the past decade, and are thought to affect at
least hundreds of children around the world. Children with the disease
suffer from severe developmental delays, seizures and uncontrolled
muscle movements.

"We were able to figure out what this protein does in the nervous system,
and then use that knowledge to find out why its mutation leads to this devastating disorder," says study senior author Kirill Martemyanov,
PhD, professor and Chair of the Department of Neuroscience at Scripps
Research in Florida.

Understanding a lesser-known G protein Gao is a member of a family of
proteins called G proteins, best known for their roles in carrying signals
into cells from cell-surface receptors called G- protein-coupled receptors (GPCRs). These receptors are found on many cell types in the brain and elsewhere in the body, and mediate dozens of biological processes from inflammation to mood and vision.

Because GPCRs are so important and relatively well studied, a large
fraction of medicines target them to treat diseases. However, unlike
most other G proteins, Gao has a role in GPCR signaling that has remained somewhat obscure.



==========================================================================
"My lab has been studying this protein for quite some time," says
Martemyanov, "and there was really no connection to anything immediately disease-related until a few years ago, when mutations in the gene encoding
Gao were found to cause a set of rare genetic syndromes featuring
seizures and uncontrollable movements." The neuroscientist was soon
attending meetings of the Virginia-based Bow Foundation and the European organization Famiglie GNAO1, which support families of children with
these syndromes. Ultimately, the Bow Foundation helped fund his study
through a fellowship award to the study's first author Brian Muntean,
PhD, a postdoctoral researcher in the Martemyanov lab.

A 'dominant negative effect' Gao protein is found at high levels in
brain cells, and the syndromes caused by the mutation of its gene, GNAO1, involve disruptions in brain signaling that controls movements. Therefore,
in the study, Martemyanov and colleagues focused on the role of Gao in
a major motor control hub in the brain called the striatum.

They found that mice engineered with a disrupted GNAO1 gene in striatal
neurons had a severe movement disorder, with impairments in muscle
coordination and in their ability to learn physical tasks. Comparing
those mice with their healthy counterparts, the researchers teased apart
the complex molecular mechanisms by which Gao affects GPCR signaling in
these brain cells.



========================================================================== These striatal neurons express GPCRs for the neurotransmitters dopamine
and adenosine, and the scientists were able to show that Gao supports
key elements of the signaling pathways that feed into striatal neurons
from these receptors -- helping to maintain the proper amplification
and coordination of dopamine and adenosine signals and enabling seamless control of movements.

The team engineered mice to have several of the same GNAO1 mutations that
have been reported in children with GNAO1 disorders. The scientists found
that these mutations could be classified along a range of deficiencies,
but in each case the resulting mutant Gao was not entirely functional.

GNAO1 disorders usually involve only one mutant copy of the gene out
of the two copies that exist in each person's genome. Martemyanov and colleagues discovered, however, that the mutant Gao proteins often
interfere with the workings of the remaining non-mutant Gao proteins
-- what biologists call a "dominant negative" effect. The scientists
also found that this interference takes different forms depending on
the particular GNAO1 mutation, creating a variety of disease patterns,
but generally appears to cause severe disruption to motor control even
when the normal functional copy of Gao is present.

"These findings can now guide our thinking about possible corrective strategies," Martemyanov says.

Funding was provided by the National Institutes of Health (NIH) (DA041207, DA048579, NS072129, DA036596, DA026405), the Intramural Research Program
of the NIH (Project Z01-ES-101643) and the Bow Foundation.


========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Brian S. Muntean, Ikuo Masuho, Maria Dao, Laurie P. Sutton, Stefano
Zucca, Hideki Iwamoto, Dipak N. Patil, Dandan Wang, Lutz Birnbaumer,
Randy D. Blakely, Brock Grill, Kirill A. Martemyanov. Gao is
a major determinant of cAMP signaling in the pathophysiology
of movement disorders. Cell Reports, 2021; 34 (5): 108718 DOI:
10.1016/ j.celrep.2021.108718 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/02/210203094719.htm

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