\ ALS Research \ Preventing Nerve Cell Death In ALS
Dr. Ross, a biochemist, is an Associate Professor in the Department of Physiology at Queen’s University in Kingston, Ontario and a researcher in the university’s Centre for Neuroscience Studies. Thanks to a grant from the Neuromuscular Research Partnership (NRP), he will conduct basic research to identify critical steps in the nerve cell death process. The NRP is a joint initiative of the ALS Society of Canada, the Muscular Dystrophy Association of Canada and the Canadian Institutes of Health Research. The grant will provide Dr. Ross $67,000 annually for the next three years.
Describing the project, Dr. Ross says, “We’re looking to see if metal ions, which are known to have altered metabolism in ALS, could be contributing to a loss of growth factor activity which then leads to the death of the motor neurons.”
“We are trying to prevent the death of nerve cells and, in that way, actually prevent the progression of the disease.”
Researchers have already identified that, in some forms of ALS, there is a mutation or abnormality in an enzyme that binds to zinc and copper ions. This enzyme called superoxide dismutase (SOD), normally breaks down one specific chemical, superoxide, into a less toxic form. Dr. Ross suggests that when SOD is mutated, it packs a one-two punch.
“When a person has a mutated SOD, they are more susceptible to oxidative stress, because SOD can’t bind the zinc and copper it needs to function normally. But the zinc and copper, which are now free, can poison growth factors; so the growth factors can’t help the cells resist oxidative stress. It ends up being a double whammy.”
In previous ALS Canada-funded research, Dr. Ross found that motor neurons can die when they are supported by growth factors that are sensitive to zinc and copper. But there is much less of an effect when the motor neurons are maintained by growth factors that are not sensitive to zinc and copper.
Dr. Ross now hypothesizes that when the zinc and copper ions are not able to bind to the SOD protein, then they are free to interact with other proteins, such as growth factors, and have toxic effects.
Growth factors are essential for keeping neurons alive and properly connected. For instance, there are growth factors produced by muscle cells that nourish the neurons in the spinal cord that connect to the muscle cells. There are also growth factors within the spinal cord that keep the muscle cells alive and well.
Working with a panel of transgenic mice – some with mutations in the SOD protein, others with mutations in the receptors for specific growth factors – and with nerve cells isolated from these mice, Dr. Ross will expose motor neurons to concentrations of zinc and copper that can lead to cell death, then observe how the neurons respond when different growth factors are applied.
“If we know how the metal ions poison growth factors, then we will know whether or not that’s important. If we can prove that it’s the reason cells die, then it gives us a drug target where we can start to develop therapies.”
Possible therapeutic strategies could include using chemicals called metal ion chelators to soak up the excess metal ions, altering nerve cells to respond to growth factors that are not sensitive to zinc and copper, and enhancing the nerve cells’ own anti-oxidant defence systems.
Dr. Ross welcomes the NRP grant as an opportunity to look at early steps in cell death and identify the mechanisms involved. “It’s the type of research that allows us to develop strategies. It’s incredibly valuable work.”
When someone is diagnosed with ALS, even if there is relatively little nerve cell damage, there is currently no way to prevent the damage from progressing. If a treatment can get to the core of the underlying processes, then, says Dr. Ross, “If somebody shows up in the clinic with very early symptoms of the disorder, we could prevent the disease from progressing by preventing more cells from dying.”
The SOD mutation occurs in some people with the inherited form of ALS, so a treatment that alters the zinc/copper/SOD interaction could also be the basis for therapy that someone with a genetic predisposition to ALS could take even before exhibiting symptoms.
In view of the similarities in the way neurons die in ALS and other neurodegenerative disorders, Dr. Ross’ research may also provide clues on how other types of neurons may be saved.
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Preventing Nerve Cell Death In ALS
ALS attacks the nerve cells that control the voluntary muscles throughout the body. When these muscles fail to receive messages, they eventually lose strength, atrophy and die. Dr. Gregory Ross’ ALS research focuses on understanding how and why the nerve cells die, as a basis for developing strategies and therapies to keep the cells alive and stop the progression of the disease.Dr. Ross, a biochemist, is an Associate Professor in the Department of Physiology at Queen’s University in Kingston, Ontario and a researcher in the university’s Centre for Neuroscience Studies. Thanks to a grant from the Neuromuscular Research Partnership (NRP), he will conduct basic research to identify critical steps in the nerve cell death process. The NRP is a joint initiative of the ALS Society of Canada, the Muscular Dystrophy Association of Canada and the Canadian Institutes of Health Research. The grant will provide Dr. Ross $67,000 annually for the next three years.
Describing the project, Dr. Ross says, “We’re looking to see if metal ions, which are known to have altered metabolism in ALS, could be contributing to a loss of growth factor activity which then leads to the death of the motor neurons.”
“We are trying to prevent the death of nerve cells and, in that way, actually prevent the progression of the disease.”
Researchers have already identified that, in some forms of ALS, there is a mutation or abnormality in an enzyme that binds to zinc and copper ions. This enzyme called superoxide dismutase (SOD), normally breaks down one specific chemical, superoxide, into a less toxic form. Dr. Ross suggests that when SOD is mutated, it packs a one-two punch.
“When a person has a mutated SOD, they are more susceptible to oxidative stress, because SOD can’t bind the zinc and copper it needs to function normally. But the zinc and copper, which are now free, can poison growth factors; so the growth factors can’t help the cells resist oxidative stress. It ends up being a double whammy.”
In previous ALS Canada-funded research, Dr. Ross found that motor neurons can die when they are supported by growth factors that are sensitive to zinc and copper. But there is much less of an effect when the motor neurons are maintained by growth factors that are not sensitive to zinc and copper.
Dr. Ross now hypothesizes that when the zinc and copper ions are not able to bind to the SOD protein, then they are free to interact with other proteins, such as growth factors, and have toxic effects.
Growth factors are essential for keeping neurons alive and properly connected. For instance, there are growth factors produced by muscle cells that nourish the neurons in the spinal cord that connect to the muscle cells. There are also growth factors within the spinal cord that keep the muscle cells alive and well.
Working with a panel of transgenic mice – some with mutations in the SOD protein, others with mutations in the receptors for specific growth factors – and with nerve cells isolated from these mice, Dr. Ross will expose motor neurons to concentrations of zinc and copper that can lead to cell death, then observe how the neurons respond when different growth factors are applied.
“If we know how the metal ions poison growth factors, then we will know whether or not that’s important. If we can prove that it’s the reason cells die, then it gives us a drug target where we can start to develop therapies.”
Possible therapeutic strategies could include using chemicals called metal ion chelators to soak up the excess metal ions, altering nerve cells to respond to growth factors that are not sensitive to zinc and copper, and enhancing the nerve cells’ own anti-oxidant defence systems.
Dr. Ross welcomes the NRP grant as an opportunity to look at early steps in cell death and identify the mechanisms involved. “It’s the type of research that allows us to develop strategies. It’s incredibly valuable work.”
When someone is diagnosed with ALS, even if there is relatively little nerve cell damage, there is currently no way to prevent the damage from progressing. If a treatment can get to the core of the underlying processes, then, says Dr. Ross, “If somebody shows up in the clinic with very early symptoms of the disorder, we could prevent the disease from progressing by preventing more cells from dying.”
The SOD mutation occurs in some people with the inherited form of ALS, so a treatment that alters the zinc/copper/SOD interaction could also be the basis for therapy that someone with a genetic predisposition to ALS could take even before exhibiting symptoms.
In view of the similarities in the way neurons die in ALS and other neurodegenerative disorders, Dr. Ross’ research may also provide clues on how other types of neurons may be saved.
| Posted On: Wednesday, December 05, 2001 Modified: Wednesday, December 05, 2001 Category: ALS Research Posted By: |