Finding the evolutionary trail leading to Lou Gehrig's disease
By Ruth SoRelle, M.P.H.
The answer to the mystery of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) began nearly half a millennia ago when a Portuguese immigrant to Brazil brought along an unwelcome traveler – a genetic defect that caused the nerve and muscle-wasting disease.
That immigrant passed the gene defect to relatives, who also passed it on. This rare, inherited form of the disorder has been identified in approximately 200 people so far. A perceptive physician, Mayana Zatz, Ph.D., an iconic geneticist at the University of Sao Paolo, found several large Brazilian families in whom the disease was inherited.
Starting point
With that as a starting point, Hiroshi Tsuda, Ph.D., a postdoctoral student in the Baylor College of Medicine laboratory of Hugo Bellen, D.V.M., Ph.D., professor of molecular and human genetics and a Howard Hughes Medical Institute investigator at BCM, took over.
The research became a scientific quest for Bellen, Tsuda and thier colleagues who sought to find the function of the important nervous system protein that was mutated in this disease.
The work led them to deduce the role of 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 the disorder.
In a report in a issue of the journal Cell, Bellen, Tsuda and his team, along with that of Michael Miller, Ph.D., 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 that is similar to ALS in humans.
Devastating disease
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.
Major sperm protein
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 phrin receptors, regulating their role in nerve cells and muscles. (Eprin 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).
Protein accumulates in cytoplasm
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.
Two effects
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.
Others who took part in this work include Chao Tong, Yong Qi Lin, Kriti Mohan, Claire Haueter, Anthony Zoghbi, Yadollah Harati and Justin Kwan, all of BCM, and Sung Min Han and Youfeng Yang, of the University of Alabama at Birmingham.
Funding for this work came from the Mental Retardation and Developmental Disabilities Research Center at BCM, the American Cancer Society, the Howard Hughes Medical Institute and George and Ronya Kozmetsky.
An abstract of the paper can be found at www.cell.com.
