The new breed of insects may help society better understand and treat CMT

[Guest guest]

Scripps Research scientists observe human neurodegenerative disorder in fruit

flies

The new breed of insects may help society better understand and treat

Charcot-Marie-Tooth disease

http://www.eurekalert.org/pub_releases/2009-06/sri-srs062409.php

La Jolla, CA, June 24, 2009 -- A team of scientists from The Scripps Research

Institute, Katholeike Universiteit Leuven, and the University of Antwerp,

Belgium, among other institutions, has created a genetically modified fruit fly

that mimics key features of Charcot-Marie-Tooth disease, a common

neurodegenerative disorder that strikes about one out of every 2,500 people in

the United States.

As described in an article published in an Early Edition of the journal

Proceedings of the National Academy of Sciences the week of June 22, 2009, the

work will enable scientists to study the development of the disease in powerful

new ways. This work may reveal new information on how the disease develops in

humans, and it will provide researchers with a tool for discovering potential

new drugs to treat the disease.

Named for the three physicians who first identified the disease in 1886,

Charcot-Marie-Tooth is one of the most common inherited neurological disorders

in the United States today. When people have this disease, some lose the

protective covering on their nerves called myelin. This causes a host of

problems that usually emerge in early adulthood, including loss of muscle mass,

pain and sensitivity, foot deformations, and walking difficulties.

After the human genome was solved a few years ago, studies revealed that some

people with Charcot-Marie-Tooth have mutations in their genes that make a

critical human protein called tyrosyl-tRNA synthetase.

This came as a surprise to many scientists, says Schimmel, who is the

Ernest and Hahn Professor and Chair of Molecular Biology and Chemistry and

is a member of The Skaggs Institute for Chemical Biology at Scripps Research.

This protein belongs to a class of molecules involved in one of the most

fundamental processes in life—the culminating steps in gene expression.

Basically, when a gene is expressed, its double-stranded DNA is first

transcribed into a corresponding single-stranded piece of messenger RNA. Then an

enzyme called the ribosome uses the mRNA as a template to make a protein by

reading out its genetic sequence and then translating it into a string of amino

acids. That's where the tRNA synthetases are needed.

When building new proteins, ribosomes rely on a set of molecules called transfer

RNAs (tRNAs) to supply them with the amino acids they need to construct the

proteins. The tRNA synthetases are needed to attach amino acids to the tRNAs.

Sound complicated? It is. But the action of tRNA synthetases is also so

essential that every creature on the planet has these molecules, which probably

evolved very early on as life first emerged on Earth.

" These proteins are among the first to appear in the planet, " says Schimmel, who

led the current research effort. " All cells need them to grow, divide, and

survive. "

When mutations in tyrosyl-tRNA synthetase were linked to Charcot-Marie-Tooth

disease a few years ago, scientists debated whether problems arose because the

mutations interfered with tRNA synthetase's normal function, helping to express

genes into proteins, or whether they arose because the mutations interfered with

some other unknown function.

Schimmel had been studying this type of molecule for many years and had already

discovered novel functions that had evolved over time in some tRNA synthetases,

including this one. He reckoned that, if one could first show that a CMT-causing

mutant synthetase was active for protein synthesis, then recreating the same

disease in another organism (by putting the same mutations in the other

organism's analogous gene) would demonstrate that a novel function was at play.

This is exactly what he and his scientific collaborators did. After showing that

the disease was not caused by a defect in the synthetase's activity for protein

synthesis, the researchers created the same mutations to the equivalent protein

in the fruit fly Drosophila melanogaster, which caused the insect to develop a

condition with several of the hallmarks of the human disease. This suggests that

Charcot-Marie-Tooth disease is related to some fundamental and unknown function

the protein plays in the development and homeostasis of the nervous system.

Because the unknown function is common to both humans and flies, it probably

evolved hundreds of millions of years ago before the ancient ancestors of humans

and flies diverged.

What exactly this function is for is still unknown. " That is a great mystery, "

says Schimmel. He adds that the genetically altered fruit flies are a convenient

and powerful model system that may be able to help answer this question.

###

In addition to Schimmel, the article, " Dominant mutations in the tyrosyl-tRNA

synthetase gene recapitulate in Drosophila features of human Charcot–Marie–Tooth

neuropathy, " was authored by Storkebaum, Leitão-Gonçalves, Inge

Bosmans, Van Dijck, Koen Norga, and Callaertsa of Katholeike

Universiteit Leuven, Tinne Ooms, An s, Timmerman, and Albena

Jordanova of the University of Antwerp, Tanja Godenschwege and Mejia of

Florida Atlantic University, Nangle of Scripps Research and Tyr Pharma,

and Xiang-Lei Yang of Scripps Research.

This work was supported by the University of Antwerp, Katholieke Universiteit

Leuven, Research Foundation Flanders, the Belgian Federal Science Policy

Of & #64257;ce, Medical Foundation Queen beth, the Association Belge contre

les Maladies Neuromusculaires, the National Institute of Child Health and Human

Development, the National Institutes of Health, the National Foundation for

Cancer Research, and the Fund for Scientific Research.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent,

non-profit biomedical research organizations, at the forefront of basic

biomedical science that seeks to comprehend the most fundamental processes of

life. Scripps Research is internationally recognized for its discoveries in

immunology, molecular and cellular biology, chemistry, neurosciences,

autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine

development. Established in its current configuration in 1961, it employs

approximately 3,000 scientists, postdoctoral fellows, scientific and other

technicians, doctoral degree graduate students, and administrative and technical

support personnel. Scripps Research is headquartered in La Jolla, California

with a second campus located in Jupiter, Florida. Research at Scripps Florida

focuses on basic biomedical science, drug discovery, and technology development.

[Guest guest]

WOW - I can't put into words how excited I am to hear about Scripps involvement!

We have personal experience with Scripps. My husband took part in one of

Scripps research programs years ago. He was extremely allergic to aspirin and

aspirin based products and he went out to Scripps and they were able to

desensitize him to aspirin and put him on a life-long regiment. It was fully

funded by Scripps. All we had to pay for was the plane ticket. Their an

amazing place with a wonderful staff and I'm so hopeful now : O)

Carmella