Motor Neuron Disease And Toxic Substances: Possible Link?

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http://www.sciencedaily.com/releases/2008/03/080320163109.htmMotor Neuron Disease And Toxic Substances: Possible Link?ScienceDaily (Mar. 21, 2008) — Motor neuron disease is a rare, devastatingillness in which nerve cells that carry brain signals to muscles graduallydeteriorate. One form of it, Lou Gehrig’s disease or ALS (amyotrophiclateral sclerosis), is familiar to the public in the lives of scientistStephen Hawking and Morrie Schwartz, about whom Mitch Albom’s “Tuesdays withMorrie†was written.For most MND patients, the cause is unknown. Figuring out why these peopledevelop the disease, which causes muscles to weaken, atrophy and cease tofunction, is an important step in developing therapies to treat or preventmotor 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 neurondisease.The discovery paves the way for better diagnosis and research on treatments.Most intriguing, the scientists found the mutations caused changes in aprotein already known to be involved when people develop neurologicdisorders as a result of exposure to toxic organophosphates—chemicalscommonly 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 someforms of motor neuron disease,†says John K. Fink, M.D., professor ofneurology 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 contributeto motor neuron disease in genetically vulnerable people,†says Fink. Hebelieves the results suggest that altered activity of the gene found inpatients in the study may also contribute to other motor neuron disorders,possibly including ALS. Motor neuron disease affects five per 100,000 peopleThe findings are an exciting first step in uncovering a possible linkbetween the environment and motor neuron disease, says Shirley Rainier, aresearch assistant professor at the U-M Department of Neurology and thefirst author of the study. “Why does one person in a family get it, andanother doesn’t?â€Piecing together a puzzleIn the 1930s, an estimated 50,000 people in the U.S. Became lame orotherwise neurologically affected by neurotoxic organophosphates

when theydrank a contaminated batch of “ginger Jake,†an alcohol-containing potionthat was legal during Prohibition.Ginger Jake suppliers substituted a lubricating oil for the oil usually usedcastor bean oil, when castor bean prices went up. A 2003 article in the NewYorker detailed the sad results, which led bands like the Mississippi Sheiksto write songs about the “ginger Jake blues.â€More recently, there have been incidents in Fiji, India and Africa whenaccidental consumption of oils containing neurotoxic organophosphates(instead of cooking oil) caused death or nerve damage for tens of thousandsof people. Although scientists don’t yet know the exact manner in whichtoxic organophosphate exposure leads to progressive and permanent nervedamage, they have learned that this process involves disturbance of anenzyme, NTE, contained within nerves.Fink examined members of two families who had

progressive weakness andspasticity (tightness) in their legs, as well as muscle atrophy in theirhands, shins and feet. James Albers, M.D., Ph..D., a U-M professor ofneurology and an expert in neuromuscular disorders, studied nerve and motorfunction. Rainier performed genetic studies and determined that the gene forthe 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 andexcluded other areas in the genome. Among the many genes in this region ofchromosome 19, one gene stood out as particularly likely: the gene thatencodes for NTE. Because of its known role in organophosphate-inducedneurological disease, the NTE gene was considered an important candidategene and was studied immediately.Analysis showed that the affected people in each family had NTE genemutations. These

mutations altered a critical part of the NTE protein calledthe esterase domain. Fink has named the inherited condition “NTE motorneuron disease.†It begins in childhood and progresses slowly, with symptomsof weakness and spasticity in the legs and muscle atrophy in the hands andlower legs.Next, Fink and his team want to learn if mutations in the NTE gene happen inother types of motor neuron disease such as ALS, and if the mutations make aperson more vulnerable to neurological damage from organophosphate exposure.Fink’s lab is currently using fruit flies as a model to study the NTEmutations, with the goal of finding treatments for people with motor neurondisease.Other authors include Melanie Bui, Erin Mark, Donald Thomas, Debra Tokarz,Lei Ming, Colin Delaney, and James W. Albers, M.D., Ph.D., of the U-MDepartment of Neurology; Rudy J. Richardson, D.Sc, associate professor ofneurology at U-M

Medical School and Dow Professor of Toxicology inEnvironmental Health Sciences at the U-M School of Public Health; and NoriMatsunami, Jeff Stevens, Hilary Coon and Mark Leppert, Ph.D. of theUniversity of Utah.A patent application for the use of the NTE gene and protein sequence fordiagnosis and treatment is pending. The University of Michigan through itsOffice of Technology Transfer is actively seeking a licensing partner tohelp bring the technology to market.Journal reference: American Journal of Human Genetics, Volume 82, Issue 3,780-785, 3 March 2008Funds for this research came from the National Institutes of Health, theVeterans Affairs Merit Review, the U-M Institute of Gerontology, the SpasticParaplegia Foundation and the National Organization for Rare Disorders.Adapted from materials provided by University of Michigan Health System.

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