Motor neuron disease and toxic substances: Possible link?

For most MND patients, the cause is unknown. Figuring out why these people develop the disease, which causes muscles to weaken, atrophy and cease to function, is an important step in developing therapies to treat or prevent motor neuron disease.

Now a team of University of Michigan scientists has gotten a step closer:

-- They have discovered mutations in one key gene (neuropathy target esterase, or NTE) that cause a previously unknown type of inherited motor neuron disease.
-- The discovery paves the way for better diagnosis and research on treatments.
-- Most intriguing, the scientists found the mutations caused changes in a protein already known to be involved when people develop neurologic disorders as a result of exposure to toxic organophosphates—chemicals commonly used in solvents and insecticides and also as “nerve gas” agents. This discovery points to a new lead in the search to understand MND.

“We speculate there may be gene-environment interactions that cause some forms of motor neuron disease,” says John K. Fink, M.D., professor of neurology at the U-M Medical School and senior author of the new study, which appears in the March issue of the American Journal of Human Genetics. He also is a researcher at the VA Ann Arbor Healthcare System.

“Our findings support the possibility that toxic organophosphates contribute to motor neuron disease in genetically vulnerable people,” says Fink. He believes the results suggest that altered activity of the gene found in patients in the study may also contribute to other motor neuron disorders, possibly including ALS. Motor neuron disease affects five per 100,000 people.

The findings are an exciting first step in uncovering a possible link between the environment and motor neuron disease, says Shirley Rainier, a research assistant professor at the U-M Department of Neurology and the first author of the study. “Why does one person in a family get it, and another doesn’t?”

Piecing together a puzzle

In the 1930s, an estimated 50,000 people in the U.S. became lame or otherwise neurologically affected by neurotoxic organophosphates when they drank a contaminated batch of “ginger jake,” an alcohol-containing potion that was legal during Prohibition.

Ginger jake suppliers substituted a lubricating oil for the oil usually used, castor bean oil, when castor bean prices went up. A 2003 article in the New Yorker detailed the sad results, which led bands like the Mississippi Sheiks to write songs about the “ginger jake blues.”

More recently, there have been incidents in Fiji, India and Africa when accidental consumption of oils containing neurotoxic organophosphates (instead of cooking oil) caused death or nerve damage for tens of thousands of people. Although scientists don’t yet know the exact manner in which toxic organophosphate exposure leads to progressive and permanent nerve damage, they have learned that this process involves disturbance of an enzyme, NTE, contained within nerves.

Fink examined members of two families who had progressive weakness and spasticity (tightness) in their legs, as well as muscle atrophy in their hands, shins and feet. James Albers, M.D., Ph.D., a U-M professor of neurology and an expert in neuromuscular disorders, studied nerve and motor function. Rainier performed genetic studies and determined that the gene for the condition was on a region of chromosome 19.

Mark Leppert, Ph.D., co-chair of human genetics at the University of Utah, and his team performed genetic analysis that confirmed this location and excluded other areas in the genome. Among the many genes in this region of chromosome 19, one gene stood out as particularly likely: the gene that encodes for NTE. Because of its known role in organophosphate-induced neurological disease, the NTE gene was considered an important candidate gene and was studied immediately.

Analysis showed that the affected people in each family had NTE gene mutations. These mutations altered a critical part of the NTE protein called the esterase domain. Fink has named the inherited condition “NTE motor neuron disease.” It begins in childhood and progresses slowly, with symptoms of weakness and spasticity in the legs and muscle atrophy in the hands and lower legs.

Next, Fink and his team want to learn if mutations in the NTE gene happen in other types of motor neuron disease such as ALS, and if the mutations make a person more vulnerable to neurological damage from organophosphate exposure. Fink’s lab is currently using fruit flies as a model to study the NTE mutations, with the goal of finding treatments for people with motor neuron disease.

Source: University of Michigan

Umbilical cord blood cell transplants may help ALS patients
Moderate dose proves most effective in mouse model
A study at the University of South Florida has shown that transplants of mononuclear human umbilical cord blood (MNChUCB) cells may help patients suffering from Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease. A disease in which the motor neurons in the spinal cord and brain degenerate, ALS leaves its victims with progressive muscle weakness, paralysis and, finally, respiratory failure three to five years after diagnosis.
Lou Gehrig's protein found throughout brain, suggesting effects beyond motor neurons
Two years ago researchers at the University of Pennsylvania School of Medicine discovered that misfolded proteins called TDP-43 accumulated in the motor areas of the brains of patients with amyotropic lateral sclerosis (ALS), or Lou Gehrig's disease. Now, the same group has shown that TDP-43 accumulates throughout the brain, suggesting ALS has broader neurological effects than previously appreciated and treatments need to take into account more than motor neuron areas. Their article appeared in last month's issue of the Archives of Neurology.
New research shows risk of ALS exposure in Gulf War veterans is time limited
A new study, led by researchers at the University of Cincinnati (UC), says that cases of Amyotrophic Lateral Sclerosis (ALS) among soldiers who served in the first Persian Gulf War were caused by certain events during their deployment to the war zone, meaning the exposure and illness is not as widespread as previously thought. The study is being published in the July issue of Neuroepidemiology.
Finding clues for nerve cell repair
A new study at the Montreal Neurological Institute at McGill University identifies a key mechanism for the normal development of motor nerve cells (motor neurons) - cells that control muscles. This finding is crucial to understanding and treating a range of conditions involving nerve cell loss or damage, from spinal cord injury to neurodegenerative diseases such as ALS, also known as Lou Gehrig's disease.
Genetics of ALS progression
An upcoming paper in the June 1 issue of G&D, from Drs. Hidenori Ichijo and Hideki Nishitoh (University of Tokyo) and colleagues, lends new and valuable insight into the genetics of ALS.
The Rett gene -- a rogue activator
In 1999, when Dr. Huda Zoghbi and her Baylor College of Medicine colleagues identified a mutation of the gene MeCP2 as the culprit in Rett syndrome, a neurodevelopmental disorder, the discovery was only the prelude to understanding a symphony of neurological missteps.
Inflammation triggers cell fusions that could protect neurons
Chronic inflammation triggers bone marrow-derived blood cells to travel to the brain and fuse with a certain type of neuron up to 100 times more frequently than previously believed, according to a new study from the Stanford University School of Medicine.
Researchers identify a gene responsible for Lou Gehrig's disease
A team of Canadian and French researchers has identified a novel gene responsible for a significant fraction of ALS (sporadic amyotrophic lateral sclerosis) cases. ALS is commonly referred to as Lou Gehrig’s disease, an incurable neuromuscular disorder that affects motor neurons and leads to paralysis and death within one to five years.

Motor neuron disease and toxic substances: Possible link?

Related stories:

News discussion: