Motor neuron disease and toxic substances: Possible link?

[Guest guest]

Motor neuron disease and toxic substances: Possible link?

http://www.eurekalert.org/pub_releases/2008-03/uomh-mnd032008.php

Role of abnormal protein in disease and chemical exposure suggests

gene-environment interactions

University of Michigan scientists Fink and Shirley Rainier found

mutations in one gene account for one form of motor neuron disease

and possibly play an important role in others.

Motor neuron disease is a rare, devastating illness in which nerve

cells that carry brain signals to muscles gradually deteriorate. One

form of it, Lou Gehrig's disease or ALS (amyotrophic lateral

sclerosis), is familiar to the public in the lives of scientist

Hawking and Morrie Schwartz, about whom Mitch

Albom's " Tuesdays with Morrie " was written.

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 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.

A gene mutated in one form of motor neuron disease was possibly a

point of vulnerability in nerve damage that thousands suffered from

drinking contaminated " ginger jake " in 1930.

" 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. 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.

[Guest guest]

OMG - I knew this link was eventually going to be established.