\ ALS Research \ Study Shows Mitochondria Likely To Go
A scientist new to The Packard Center for ALS Research has shown that key reactions in mitochondria, the small bodies within cells that supply energy to cells, are disrupted just before cells begin to die from the disease. Work by Giovanni Manfredi ,M.D., Ph.D., and his research team support the idea that injury to mitochondria is a step leading to the actual death of motor neurons-the main site of injury in ALS.
Manfredi's work was carried out in mouse ALS models that carry a mutated human gene coding for a protein called superoxide dismutase 1 (SOD1). People with mutant SOD1 genes develop a specific inherited form of the disease.
Studies by others have shown that ALS patients--those with either the inherited or the more common "spontaneous" form---often have mitochondria that are swollen and/or misshapen. Mitochondria in mouse models are also clearly in trouble.
The work by the Manfredi team, published recently in the Journal of Biological Chemistry, showed that, in addition to having an altered appearance, mitochondria were also impaired in function, in their chemical reactions that produce energy. This was especially obvious in the spinal cord, which happens to be the body site most affected in ALS. The study is the first to show mutated SOD1 leads to a loss of the normal activity of mitochondria in standard mouse models of ALS.
The changes in the tiny organelles didn't appear before the model mice were 13 weeks old, about six weeks before their death. This suggests that mitochondrial changes may not be the event that triggers ALS, but may be closely related to the actual death of cells.
Confirming results of other Center scientists, Manfredi also found that both mutant and normal SOD1 appear to collect in small compartments within mitochondria. But only the mutant form seems to be linked with problems. "We don't understand how it causes dysfunction," Manfredi says, "but we're testing the possibilities." One idea is that mutant SOD1 is somehow "warped" and can't function properly. Normal SOD1 is an enzyme that destroys a highly reactive molecule called superoxide, a destructive molecule that's a byproduct of energy-making in mitochondria. It's possible, the researchers say, that a shortage of normal SOD1 leaves superoxide free to damage mitochondria.
Manfredi's team, in fact, found evidence of that sort of damage.
Another idea is that mutant SOD1 accumulates in mitochondria,"gumming up" normal processes. The team, as have other Center researchers, also found evidence of accumulated mutant SOD1 within and near the outer membrane of mitochondria.
Whatever the cause of mitochondrial distress, Manfredi says, understanding its source and the relation to motor neuron damage could eventually provide targets for needed therapy.
The research team is located at the Weill Medical College of Cornell University.
The Center for ALS Research at Johns Hopkins is a collaborative effort by some of the best ALS and non-ALS scientists to aggressively and rapidly develop new treatments and find a cure for ALS, also known as Lou Gehrig's disease. It's the only institution of its kind dedicated solely to the disease. Research conducted by the Center is meant to translate from bench to bedside in an expedited time frame. Center scientists from institutions around the world have made some of the most important discoveries in ALS, leading to advances in understanding and treatment of the disease.
The nature of ALS shapes the Center's aggressive, results-oriented scientific approach. ALS is a devastating, progressive neuromuscular disease that causes complete paralysis and loss of function – including the ability to eat, speak and breathe -- and eventually, death. ALS progresses quickly and is not curable. Most patients die within five years of diagnosis.
To learn more about The Center for ALS Research at Johns Hopkins, including the latest information on ALS research and treatment, log on to www.alscenter.org
December 16, 2002
The Center for ALS Research at Johns Hopkins
Johns Hopkins ALS News Network
|
|
Click Here For A Printer Friendly Version Of This Page
Study Shows Mitochondria Likely To Go
A scientist new to The Packard Center for ALS Research has shown that key reactions in mitochondria, the small bodies within cells that supply energy to cells, are disrupted just before cells begin to die from the disease. Work by Giovanni Manfredi ,M.D., Ph.D., and his research team support the idea that injury to mitochondria is a step leading to the actual death of motor neurons-the main site of injury in ALS.
Manfredi's work was carried out in mouse ALS models that carry a mutated human gene coding for a protein called superoxide dismutase 1 (SOD1). People with mutant SOD1 genes develop a specific inherited form of the disease.
Studies by others have shown that ALS patients--those with either the inherited or the more common "spontaneous" form---often have mitochondria that are swollen and/or misshapen. Mitochondria in mouse models are also clearly in trouble.
The work by the Manfredi team, published recently in the Journal of Biological Chemistry, showed that, in addition to having an altered appearance, mitochondria were also impaired in function, in their chemical reactions that produce energy. This was especially obvious in the spinal cord, which happens to be the body site most affected in ALS. The study is the first to show mutated SOD1 leads to a loss of the normal activity of mitochondria in standard mouse models of ALS.
The changes in the tiny organelles didn't appear before the model mice were 13 weeks old, about six weeks before their death. This suggests that mitochondrial changes may not be the event that triggers ALS, but may be closely related to the actual death of cells.
Confirming results of other Center scientists, Manfredi also found that both mutant and normal SOD1 appear to collect in small compartments within mitochondria. But only the mutant form seems to be linked with problems. "We don't understand how it causes dysfunction," Manfredi says, "but we're testing the possibilities." One idea is that mutant SOD1 is somehow "warped" and can't function properly. Normal SOD1 is an enzyme that destroys a highly reactive molecule called superoxide, a destructive molecule that's a byproduct of energy-making in mitochondria. It's possible, the researchers say, that a shortage of normal SOD1 leaves superoxide free to damage mitochondria.
Manfredi's team, in fact, found evidence of that sort of damage.
Another idea is that mutant SOD1 accumulates in mitochondria,"gumming up" normal processes. The team, as have other Center researchers, also found evidence of accumulated mutant SOD1 within and near the outer membrane of mitochondria.
Whatever the cause of mitochondrial distress, Manfredi says, understanding its source and the relation to motor neuron damage could eventually provide targets for needed therapy.
The research team is located at the Weill Medical College of Cornell University.
The Center for ALS Research at Johns Hopkins is a collaborative effort by some of the best ALS and non-ALS scientists to aggressively and rapidly develop new treatments and find a cure for ALS, also known as Lou Gehrig's disease. It's the only institution of its kind dedicated solely to the disease. Research conducted by the Center is meant to translate from bench to bedside in an expedited time frame. Center scientists from institutions around the world have made some of the most important discoveries in ALS, leading to advances in understanding and treatment of the disease.
The nature of ALS shapes the Center's aggressive, results-oriented scientific approach. ALS is a devastating, progressive neuromuscular disease that causes complete paralysis and loss of function – including the ability to eat, speak and breathe -- and eventually, death. ALS progresses quickly and is not curable. Most patients die within five years of diagnosis.
To learn more about The Center for ALS Research at Johns Hopkins, including the latest information on ALS research and treatment, log on to www.alscenter.org
December 16, 2002
The Center for ALS Research at Johns Hopkins
Johns Hopkins ALS News Network
| Posted On: Friday, December 20, 2002 Modified: Friday, December 20, 2002 Category: ALS Research Posted By: |