Nerve-Destroying Chemicals are Model for Neurodegenerative Diseases

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Tiny motor proteins delivering vital nutrients along the length of nerves are a target for two common chemicals known for their neurotoxicity, says a Medical College of Georgia researcher.

Acrylamides – used in water purification, paper manufacturing, mining and recently found in potato chips, French fries, baked cereals and other carbohydrates cooked at high temperatures – and hexanes — an organic solvent used in glues, paints and shoe manufacturing – can shut down these motor proteins, says Dr. Dale W. Sickles, MCG neurotoxicologist.

Most at risk for the resulting nerve damage are those who help produce these chemicals and those who routinely use them to make other things.

But the potential beneficiaries from Dr. Sickles’ studies also include those with neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, because identifying exactly how these chemicals damage and destroy nerves is providing clues for what happens in disease.

The benefit may be even greater as he investigates the potential effects of chronic low-dose exposure to these chemicals on memory as well.

“Degeneration of nerves is the most common effect of toxic chemicals compromising the nervous system,” he says. “So if we identify all the various ways we can produce that degeneration, you now have a menu for how nerves can be compromised and you can start comparing that with various neurodegenerative diseases.” Recent studies are identifying specific motor deficits related to specific diseases.

A natural attraction exists between motor proteins and these chemicals; sulfhydryl (sulfur and oxygen) groups on the proteins naturally bind to acrylamides and amino groups have a similar affinity for hexanes, Dr. Sickles says.

Often the union is of no consequence. But he has found that motor proteins called kinesins, those constantly being produced and delivering nutrients, can be devastated by this union, perhaps in part because they are susceptible to lower doses of these chemicals than other proteins.

The good news is that, because the body keeps making motor proteins, the potential for nerve damage repair is high, but the chances get slimmer with the increasing length of the nerves.

Nerves can be long; the longest are several feet, reaching from the spinal cord to the hands and feet. He hypothesizes that these longest nerves typically show the first sign of trouble. “If you block enough of these motor proteins, you will eventually cause a deficiency in the distal nerves and that is what causes degeneration or dysfunction.” Dr. Sickles likens the process to chemical axotomy, chemically cutting off the end of the nerve.

“These are two dramatically different chemicals yet they can bind to the same protein and block its function and therefore have similar outcomes,” he says.

And these chemicals are pervasive: “We eat them; we wear them on our feet,” he says. In fact, one of Dr. Sickles’ new avenues for study is the effect of chronic, low-dose exposure to these chemicals, an exposure level that many people may have.

“There are a lot of hypotheses about neurodegenerative disorders that suggest it takes multiple insults in the environment that collectively add up to a consequence,” he says. “That may be what we are looking at here. These motor proteins are important in nerve transmission, they could have effects on memory and things at doses we are just not aware of; doses that may not be enough to cause you to lose sensation in your hands or feet, but what if it has some other effect?” Dr. Sickles says.

Still another risk of exposure may be related to the role of motor proteins in cell division. These motor proteins are responsible for separation of chromosomes. Acrylamide particularly can cause maldistribution of chromosomes when a cell divides. “We believe it is due to the changing of the motor protein involved in cell division,” Dr. Sickles says. “If regulatory genes are maldistributed to daughter cells, the cell may go into uncontrolled division. That might be one of the contributory issues with cancer produced by acrylamide.”

Acrylamide’s role in causing cancer in laboratory animals and potentially in humans has been the subject of much scientific debate. A group of public health experts organized by the World Health Organization last summer said the chemical poses a potential, yet undetermined cancer risk to humans. The FDA and the National Institutes of Health are paying more attention to this danger since the discovery of acrylamide in food. A subsequent meeting of scientists this February called for more research on acrylamides.

Dr. Sickles, who is vice chairman of the MCG Department of Cellular Biology and Anatomy, is scheduled to discuss his research at a meeting this August in Sweden of 60 international scientists studying molecular mechanisms of neurodegeneration.

“Part of the significance is that people are exposed to these chemicals,” Dr. Sickles says. “We need to know how they work. At what doses do they have a major effect?”

To answer those questions, Dr. Sickles, whose work is funded by the National Institutes of Health, is examining the volume of proteins delivered to the axon, the distant end of the nerve, measuring the function of that axon and how it communicates with muscle.

“We are going to be altering the concentrations of kinesins. If the action on kinesin is a critical function, if we alter the concentrations of that protein only, it should alter the susceptibility of nerves to the toxicants. We are hoping to prove that this is the critical site of action,” he says.

Understanding how chemicals affect motor proteins may have even broader implications since organophosphorus pesticides – used as war agents as well – also impact these motor proteins or kinesins, says Dr. Sickles of related studies on which he is collaborating with MCG colleagues Drs. Jerry J. Buccafusco and Alvin V. Terry Jr.

“We have data that shows that. They may be actually altering receptors within the nervous system and they may have effects on memory,” he says of what he calls, at the moment, an indirect link between the actions of acrylamides, hexanes and organophosphorus pesticides. This could mean that all the farmers exposed to these pesticides, and possibly the people who eat their produce as well, are getting low doses of agents that could affect memory. They are now going back to look at the potential of acrylamides and hexanes on memory. “That is where we are headed right now,” he says.

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