BGU and University of California researchers discover new mechanism in Lou Gehrig’s disease

Discovery bears potential to serve as a target for novel therapeutic intervention to treat not only ALS.

March 22, 2015 15:21
2 minute read.
Petri dish [Illustrative]

Petri dish [Illustrative]. (photo credit: REUTERS)

A molecular mechanism that could lead to the development of therapies for incurable amyotrophic lateral sclerosis has been discovered by researchers at Ben-Gurion University of the Negev in Beersheba and the University of California at San Diego. The study was just published in the prestigious journal Neuron.

ALS (or Lou Gehrig’s disease), the fatal neurodegenerative named after New York Yankees baseball star Lou Gehrig, who died of it in 1941, involves the destruction of motor neurons that control voluntary muscles.

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The victim suffers from progressive weakness and paralysis due to muscle atrophy, leading to difficulty in speaking, swallowing and eventually breathing – but the mind remains clear as a bell. There is no effective treatment.

The cause of ALS is not known in about 90 percent of cases, but the remaining cases are genetically inherited. The disease usually begins between the age of 40 to 60, and the average survival is only two to five years. About 10% – including the famed astrophysicist Prof.

Stephen Hawking, survive longer than 10 years.

About a fifth of the genetic cases are due to mutations in the superoxide dismutase (SOD1) gene. Interdisciplinary research projects have shown that mutations in this gene (more than 165 different mutants are now known) provoke selective killing of motor neurons by their suffering from some form of toxicity, but the basis for this selective toxicity has not been identified.

Recently, the collaborative research conducted by the laboratory of Dr. Adrian Israelson at BGU’s physiology and cell biology department and the group of Prof. Don Cleveland in California was published.

The researchers report the identification of a factor that is able to inhibit accumulation of misfolded SOD1. They purified it and identified it to be the well-known multifunctional protein macrophage migration inhibitory factor (MIF). Purified MIF is shown to directly inhibit mutant SOD1 misfolding and binding to intracellular organelles.

Elevated expression of MIF is shown to suppress accumulation of misfolded SOD1 in neuronal cells and extends survival of mutant SOD1 expressing motor neurons. These efforts identify low “chaperone activity” of MIF in motor neurons as a likely component of selective vulnerability to mutant SOD1 misfolding, and propose enhancement of intracellular MIF chaperone activity as an attractive therapeutic strategy.

Since the misfolding of proteins is a common toxic mechanism among neurodegenerative disorders, this discovery by the Israelson and Cleveland laboratories “bears the potential to serve as a target for novel therapeutic intervention aimed to raise the level of MIF within the central nervous system to treat not only ALS,” they wrote, “but many other neurodegenerative diseases that are linked to accumulation of misfolded proteins.”

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