On the evolutionary trail of molecules that cause Lou Gehrig's disease

June 12, 2008,

What became a scientific quest for Dr. Hugo Bellen and his colleagues at Baylor College of Medicine in Houston began with trying to define the function of a protein that plays a role in the nervous system.

That led to work with similar proteins in the nerve cells of worms, fruit flies, and people and culminated in important clues about what goes wrong in the nerves and muscles of people with amyotrophic lateral sclerosis (better known as ALS or Lou Gehrig's disease), said Bellen, a professor molecular and human genetics at BCM.

In a report in the current issue of the journal Cell, his team and that of Dr. Michael Miller from the University of Alabama at Birmingham show how a single mutation in the human form of the VAMP-Associated Protein B (VAPB) contributes to the nerve and muscle breakdown in flies and worms, similar to ALS in humans.

The story actually begins around 500 years ago, when a Portuguese immigrant to Brazil brought along an uninvited guest – a mutation in the gene for VAPB. That mutation leads to a rare form of inherited ALS that has so far been identified in about 200 people. ALS is a devastating disease that begins in middle age and affects nerves and muscles, destroying the individual's ability to move, talk, swallow and breathe, eventually killing the person who has it. There are an estimated 30,000 people with ALS in the United States alone. It affects people of all ethnicities worldwide.

Working in Drosophila or fruit flies, Bellen and his colleagues found that when the fly VAPB gene equivalent called VAP33 is lacking, the nerve endings are abnormal, suggesting that in its normal form, the protein associated with VAP33 is important at the junction between nerve and muscle.

Then Dr. Mayana Zatz, a professor at the University of Sao Paolo, found several large Brazilian families with a gene mutation or defect in VAPB that led to ALS. (There are mutations in other genes that cause ALS as well). At that point, a postdoctoral fellow in the Bellen lab, Dr. Hiroshi Tsuda, took over.

One of the domains of VAPB is similar to a protein in C. elegans called the major sperm protein (MSP). MSP plays a major role in readying the hermaphroditic worm to reproduce. In effect, it acts as a hormone. Tsuda dubbed the part of the VAP33 protein that resembled major sperm protein the MSP domain in its honor.

They then found that somehow the MSP domain of VAPB was being secreted and circulated in the blood throughout the human body.

"The protein is cleaved, secreted and functions as a hormone," said Bellen.

In collaboration with Miller's team at UAB, they found that MSP actually binds to ephrin receptors, regulating their role in nerve cells and muscles. (Ephrin receptors affect cell interactions, mediating when cells adhere to or repel one another as well as in clustering specific receptors present on neurons and muscle cells).

The scientists' work indicates that the mutated form of the human VAPB protein accumulates in the cell's cytoplasm. As more and more abnormal protein accumulates, both normal and abnormal protein (mutant VAPB) becomes trapped in the cell's cytoplasm. This prevents it from secreting the MSP domain, which means that the body no longer has its hormonal action. The accumulation also prevents proper protein folding, which can be toxic to neurons.

Bellen and his colleagues found that the mutant form of the protein has two effects. One, it causes the unfolded protein response that ultimately is harmful to the neurons and may affect motor function. Second, it leads to reduced secretion of MSP and a loss of the signaling mediated by ephrin receptors. They believe that these two problems work together to produce some of the key features of ALS.

Source: Baylor College of Medicine

Explore further: Disruption of gene used to transport proteins leads to ALS

Related Stories

Stem cell model offers clues to cause of inherited ALS

June 21, 2011

An international team of scientists led by researchers at the University of California, San Diego School of Medicine have used induced pluripotent stem cells (iPSCs) derived from patients with amyotrophic lateral sclerosis ...

Study identifies new gene associated with ALS

February 26, 2009

A collaborative research effort spanning nearly a decade between researchers at Massachusetts General Hospital (MGH) and King’s College London (KCL) has identified a novel gene for inherited amyotrophic lateral sclerosis ...

Recommended for you

Scientists ID another possible threat to orcas: pink salmon

January 19, 2019

Over the years, scientists have identified dams, pollution and vessel noise as causes of the troubling decline of the Pacific Northwest's resident killer whales. Now, they may have found a new and more surprising culprit: ...

Targeting 'hidden pocket' for treatment of stroke and seizure

January 19, 2019

The ideal drug is one that only affects the exact cells and neurons it is designed to treat, without unwanted side effects. This concept is especially important when treating the delicate and complex human brain. Now, scientists ...

Technology near for real-time TV political fact checks

January 18, 2019

A Duke University team expects to have a product available for election year that will allow television networks to offer real-time fact checks onscreen when a politician makes a questionable claim during a speech or debate.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet Jun 13, 2008
Lou Gehrig's Diesease and ALS give no hint as to the actual pathology involved except to medically trained specialist. By contrast, the term "motor neuron disease" used in Britain gives a very pertinent insight into the pathology.

Why can't writers in the USA use the accurately descriptive British term?

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.