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ALS Association-Funded Researchers Discover New Links Leading To Neuron Death

WASHINGTON, Dec. 10, 2012 /PRNewswire-USNewswire/ -- Researchers supported by The ALS Association have discovered an important process that puts neurons at risk of the cell death, which characterizes numerous neurodegenerative diseases. The discovery, which was published today in the Proceedings of the National Academy of Sciences, highlights the links between several proteins known to go awry in ALS and a related disease, frontotemporal dementia (FTD).

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. For unknown reasons, veterans are twice as likely to develop ALS as the general population. There is no cure, and only one drug approved by the U.S. Food and Drug Administration (FDA) modestly extends survival.

"This new finding puts together several critical links in the chain leading to neuronal death," said Lucie Bruijn, Ph.D., Chief Scientist for The ALS Association.

The first protein in the chain is called TDP-43. Lack of TDP-43 has previously been shown to cause both ALS and FTD. The new study showed that when there is too little TDP-43, another protein, called sortilin, is made in excess. Some copies of that protein are defective, the researchers found.

Both normal and defective sortilin bind to another protein, called progranulin, a growth factor for neurons. But when excess normal sortilin and the defective sortilin bind to progranulin, neurons become deprived of this important growth factor. Thus, too little TDP-43 leads to too much normal and defective sortilin, which diminishes the amount of neuroprotective progranulin. Lack of progranulin leads to death of neurons.

The research was led by Mercedes Prudencio, Ph.D., and Leonard Petrucelli, Ph.D., of the Mayo Clinic in Jacksonville, Florida, and Emanuele Buratti, Ph.D., of the International Center for Genetic Engineering and Biotechnology in Trieste, Italy.

Dr. Prudencio is a recipient of the Milton Safenowitz Post-Doctoral Fellowship for ALS Research from The ALS Association. The ALS Association is especially committed to bringing new concepts and methods into ALS research, and young scientists play an important role in this process. Funding is generously provided by the Safenowitz family through the Greater New York Chapter of The ALS Association, in memory of Milton, who died in 1998 of the disease.

"We are extremely pleased that our support has helped Dr. Prudencio advance the field through this research," Dr. Bruijn said. "The discovery of this mechanism is important for understanding how neurons die in ALS and FTD, and in the development of new therapies targeting this pathway."

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