Nav: Home

'Relaxed' enzymes may be at the root of Charcot-Marie-Tooth disease

September 30, 2019

LA JOLLA, CA - Treatments have been hard to pinpoint for a rare neurological disease called Charcot-Marie-Tooth (CMT), in part because so many variations of the condition exist. So far, mutations on more than 90 genes have been positively linked to the disorder; a patient needs just one of those mutations for the disease to emerge.

Regardless of which genetic mutation is present, CMT universally inflicts damage on patients' peripheral nervous system, which extends from the spinal cord into the hands and feet. For that reason, patients often experience difficulties with balance, walking and fine motor skills, such as buttoning a shirt.

"The genetic mutations of CMT are well understood, but the disease-causing mechanisms are still a mystery on a molecular and cellular level," says Scripps Research Professor Xiang-Lei Yang, PhD, who led the research. "In our latest study, we took a bottom-up approach, looking for commonalities among different mutations in one of these genes in the hope that we will uncover new insights for treatment."

In research that appears in the journal PNAS, Yang and her team focused on ubiquitous enzymes known as aminoacyl-tRNA synthetases. These enzymes are not only Yang's long-running research specialty, but also the largest protein family linked to CMT disease. Pervasive throughout the body, these enzymes attach to the appropriate amino acids to kick off the first step of making new proteins. Considering that proteins are the building blocks of everything from blood and hormones to skin and bones, this process is central to human life.

Yang says that earlier research, which examined the mutated enzymes independent of other biology, had shown that the disease-affected aminoacyl-tRNA synthetases didn't work as well as their healthy counterparts. In the scientific world, this is known as a "loss of function."

But using patient samples and viewing the enzymes in their natural cellular environment, Yang's lab found something different: Any loss of function disappeared when the mutated enzymes were paired with other healthy enzymes that exist within a cell. The finding makes sense, she says, as CMT would be far more severe if this enzyme's crucial biological function was amiss.

But if there was no loss of function, how were these mutated enzymes implicated in disease? That was the next question Yang sought to answer. For this line of inquiry, she looked at shape rather than function.

Using biochemical and biophysical analysis tools, Yang and her team discovered that the mutated enzymes took on an unusual extended shape. This is unlike their healthy counterparts, which have a more compact design with far less exposed surface.

"The extra surface area may create unwanted interactions with nearby proteins, and these interactions could be what leads to a diseased state," Yang says. In fact, further study showed that disease severity is likely linked with the degree to which the enzyme's shape was relaxed or extended.

As her next step of research, Yang plans to delve more deeply into the connection between different forms of CMT, which may lead to general strategies for treating the disease. Her motivation, in addition to a scientist's need for understanding, are CMT patients and their families--many of whom have personally reached out to her.

"One in 2,500 people have CMT, and today there is no therapy available to help them," Yang says. "We believe the best path to a treatment is to start by understanding what is fundamentally wrong in the biological environment of this complex neurodegenerative disease."
Authors of the study, "CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells," are David Blocquel, Litao Sun, Zaneta Matuszek, Sheng Li, Thomas Weber, Bernhard Kuhle, Grace Kooi, Na Wei, Jonathan Baets, Tao Pan, Paul Schimmel, and Xiang-Lei Yang.

This work was supported by the National Institutes of Health [Grant R01 GM088278] and a fellowship from National Foundation for Cancer Research.

Scripps Research Institute

Related Proteins Articles:

New method to monitor Alzheimer's proteins
IBS-CINAP research team has reported a new method to identify the aggregation state of amyloid beta (Aβ) proteins in solution.
Composing new proteins with artificial intelligence
Scientists have long studied how to improve proteins or design new ones.
Hero proteins are here to save other proteins
Researchers at the University of Tokyo have discovered a new group of proteins, remarkable for their unusual shape and abilities to protect against protein clumps associated with neurodegenerative diseases in lab experiments.
Designer proteins
David Baker, Professor of Biochemistry at the University of Washington to speak at the AAAS 2020 session, 'Synthetic Biology: Digital Design of Living Systems.' Prof.
Gone fishin' -- for proteins
Casting lines into human cells to snag proteins, a team of Montreal researchers has solved a 20-year-old mystery of cell biology.
Coupled proteins
Researchers from Heidelberg University and Sendai University in Japan used new biotechnological methods to study how human cells react to and further process external signals.
Understanding the power of honey through its proteins
Honey is a culinary staple that can be found in kitchens around the world.
How proteins become embedded in a cell membrane
Many proteins with important biological functions are embedded in a biomembrane in the cells of humans and other living organisms.
Finding the proteins that unpack DNA
A new method allows researchers to systematically identify specialized proteins called 'nuclesome displacing factors' that unpack DNA inside the nucleus of a cell, making the usually dense DNA more accessible for gene expression and other functions.
A brewer's tale of proteins and beer
The transformation of barley grains into beer is an old story, typically starring water, yeast and hops.
More Proteins News and Proteins Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Climate Mindset
In the past few months, human beings have come together to fight a global threat. This hour, TED speakers explore how our response can be the catalyst to fight another global crisis: climate change. Guests include political strategist Tom Rivett-Carnac, diplomat Christiana Figueres, climate justice activist Xiye Bastida, and writer, illustrator, and artist Oliver Jeffers.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Speedy Beet
There are few musical moments more well-worn than the first four notes of Beethoven's Fifth Symphony. But in this short, we find out that Beethoven might have made a last-ditch effort to keep his music from ever feeling familiar, to keep pushing his listeners to a kind of psychological limit. Big thanks to our Brooklyn Philharmonic musicians: Deborah Buck and Suzy Perelman on violin, Arash Amini on cello, and Ah Ling Neu on viola. And check out The First Four Notes, Matthew Guerrieri's book on Beethoven's Fifth. Support Radiolab today at