FEB 07, 2021 8:34 AM PST

Insight Into a Disease-Related Protein in the Brain

WRITTEN BY: Carmen Leitch

A protein called Gαo is found at high levels in the brain. Mutations in the gene that encodes for Gαo cause dysfunctions in the resulting protein, leading to severe movement disorders. Researchers have now learned more about how this protein works. The findings provide new insight into how the brain controls muscles and may aid in the design of new treatments for the disorders caused by Gαo mutations. The work has been published in Cell Reports.

Image credit: Pixabay

In the past decade, mutations in Gαo were connected to GNAO1-related neurodevelopmental disorders. Worldwide, the disease affects hundreds of children, but there may be more cases yet to be discovered. The disease leads to seizures, severe developmental delays, 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," said the senior study author Kirill Martemyanov, Ph.D., Professor and Chair of the Department of Neuroscience at Scripps Research in Florida.

Gαo is one of many G proteins, which have been the subject of many research studies in part because they are so important to cell signaling; they carry molecular messages into cells through receptors on the cell surface called G-protein-coupled receptors (GPCRs). GPCRs are found on many types of cells and are involved in many pathways and processes. However, Gαo is one G protein that we still need to learn about.

"My lab has been studying this protein for quite some time," noted Martemyanov, "and there was really no connection to anything immediately disease-related until a few years ago, when mutations in the gene encoding Gαo were found to cause a set of rare genetic syndromes featuring seizures and uncontrollable movements."

Since brain cells express high levels of Gαo and when it's dysfunctional, brain signaling involving movement is disrupted, the researchers looked to Gαo's role in a region of the brain that helps control movement called the striatum.

The researchers created a mouse model in which GNAO1 was mutated in striatal neurons; these mice had serious movement problems including impaired muscle coordination and difficulty learning physical tasks compared to normal mice.

Further work showed that in striatal neurons Gαo is supporting parts of signaling pathways that involve the neurotransmitters dopamine and adenosine. Gαo helps coordinate and amplify dopamine and adenosine signals, allowing for harmonious control of muscle movement. When the scientists tested mutations carried by kids that have GNAO1 disorders in mouse models, they found that the resulting Gαo protein in these mice was not completely functional.

GNAO1 disorders can happen when only one of the two copies of the GNAO1 gene is mutated, and mutations in GNAO1 have a dominant-negative impact, in which the unaffected copy cannot make up for the disruption caused by the mutated copy, though the effect depends on the mutation. Typically, motor control is dysfunctional even when one copy of Gαo is normal.

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

Sources: AAAS/Eurekalert! via Scripps Research Institute, Cell Reports

About the Author
  • Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
JAN 04, 2021
Genetics & Genomics
Exploring the Genetic History of Caribbean Populations
JAN 04, 2021
Exploring the Genetic History of Caribbean Populations
Humans are thought to have first settled in the Caribbean islands about 6,000 years ago, using stone tools. Around 3,000 ...
FEB 16, 2021
Cell & Molecular Biology
A Change in One Gene Might've Made Our Brains Uniquely Human
FEB 16, 2021
A Change in One Gene Might've Made Our Brains Uniquely Human
Stem cells can be used to create simplified versions of human organs called organoids, enabling researchers to study how ...
MAR 29, 2021
Cell & Molecular Biology
The Mark of a Dead Cell In Need of Cleanup: An 'Eat Me' Sign
MAR 29, 2021
The Mark of a Dead Cell In Need of Cleanup: An 'Eat Me' Sign
An illustration by Mindy Takamiya of Kyoto University iCeMS shows how dead cells signal to the body that it's time to el ...
APR 05, 2021
Health & Medicine
April is Autism Awareness Month
APR 05, 2021
April is Autism Awareness Month
April is autism awareness month (April 2 was autism awareness day), during which people are encouraged to learn more abo ...
APR 11, 2021
Genetics & Genomics
Trial Shows Personalized Cancer Vaccines are Safe
APR 11, 2021
Trial Shows Personalized Cancer Vaccines are Safe
Vaccines are mostly known as tools to prevent illness. But cancer vaccines are a bit different, and aim to treat existin ...
APR 13, 2021
Genetics & Genomics
Skull Fossil Yields One of the Oldest Modern Human Genomes
APR 13, 2021
Skull Fossil Yields One of the Oldest Modern Human Genomes
DNA from a very old skull is changing what we know about when and where early humans lived.
Loading Comments...