\ Researchers \ New Frontiers in ALS Research
The causes of ALS may be diverse and difficult to decipher. But one common, visible feature underlies all cases: fibres called neurofilaments, that are meant to act as architectural support for the motor neuron, lending tensile strength and preserving its integrity, collapse and clump together, forming disruptive aggregates within the axon of the motor neuron. Researchers look to this signpost feature of ALS for clues about what pathways lead to the aggregates and to the ultimate failure of the motor neuron.
Dr. Michael Strong, Chief of Neurology at the London Health Sciences Centre, and a member of the medical advisory committee of the ALS Society of Canada, says the neurofilaments might aggregate for a good reason. “We now know that these neurofilament aggregates are important,” Strong says. “They are more than just rocks, stuck in the cell.” The aggregates appear to function as a sink, he explains, where oxidative enzymes that could do damage in the cell are soaked up. In particular, the SOD-1 enzyme, which is mutated in certain familial forms of ALS, migrates to the aggregates. Then there is a change in the way the mutated enzyme works, Strong explains, which might actually accelerate the cell’s oxidative stress.
The neurofilaments may aggregate because of a deficient protein. “The subunits come in three sizes,” says Strong. “There is a little one, a medium sized one, and a bigger one—like the three bears.” It is the ‘little bear’ that is in short supply when Strong looks at ALS in spinal motor neurons, and he proposes this leads to aggregation. “This is our theoretical model that we think we have some evidence to support,” says Strong. “It is possible that a normal function of the neurofilament is to bind up residual oxidative species that are producing the damage, and that the reason the aggregate forms is there is a deficiency of this particular protein. Forty per cent of its level is sufficient to produce an ALS-like syndrome in a transgenic mouse.”
Another piece was recently added to the puzzle when Strong compared his observations of ALS motor neurons with whole ALS spinal cord tissue, containing not only motor neurons, but all spinal neurons. The neurofilament subunits were low overall in the isolated motor neurons, but surprisingly high in the whole tissue samples. “That really suggested that there was some regulation of how these things were controlled,” says Strong. Further research revealed “destabilizing proteins,” which affect the levels of the RNA from which the individual proteins are made. The researchers now propose that in the face of stress, neurofilament proteins are needed and their levels can be controlled via the destabilizing proteins. “If the normal response is to have the destabilizers expressed,” says Strong, “then when you stress the neuron, the destabilizer expression should be dropped, allowing an oxidative-protective pathway. But in ALS, we are arguing that that does not occur.”
Strong believes that process may begin a cascade of events that leads to the death of the motor neuron. “Once that injury occurs, this injured neuron will recruit inflammatory cells called microglial cells.” The immune response can take two paths: it can be beneficial and aid in repair, or it can be incredibly harmful and actually kill the cells. In addition, the injured motor neurons could trigger their own death. The disease process could begin in a small group of cells, or even just one cell, Strong explains, and spread from there. In fact, he has shown it is possible to carry the cascade from one cell culture to another simply by transferring the medium of diseased cells to cultured microglial cells, and then to healthy motor neurons.
Strong sees between 120 and 150 new cases of ALS each year, with patients from Newfoundland to the mid-west. He believes an effective ALS therapy will require attacking the complex disease process at many levels. “It will almost certainly require multi-level pharmacotherapy. The challenge will be to find such therapy before another century passes in our understanding of the disease.”
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New Frontiers in ALS Research
The causes of ALS may be diverse and difficult to decipher. But one common, visible feature underlies all cases: fibres called neurofilaments, that are meant to act as architectural support for the motor neuron, lending tensile strength and preserving its integrity, collapse and clump together, forming disruptive aggregates within the axon of the motor neuron. Researchers look to this signpost feature of ALS for clues about what pathways lead to the aggregates and to the ultimate failure of the motor neuron. Dr. Michael Strong, Chief of Neurology at the London Health Sciences Centre, and a member of the medical advisory committee of the ALS Society of Canada, says the neurofilaments might aggregate for a good reason. “We now know that these neurofilament aggregates are important,” Strong says. “They are more than just rocks, stuck in the cell.” The aggregates appear to function as a sink, he explains, where oxidative enzymes that could do damage in the cell are soaked up. In particular, the SOD-1 enzyme, which is mutated in certain familial forms of ALS, migrates to the aggregates. Then there is a change in the way the mutated enzyme works, Strong explains, which might actually accelerate the cell’s oxidative stress.
The neurofilaments may aggregate because of a deficient protein. “The subunits come in three sizes,” says Strong. “There is a little one, a medium sized one, and a bigger one—like the three bears.” It is the ‘little bear’ that is in short supply when Strong looks at ALS in spinal motor neurons, and he proposes this leads to aggregation. “This is our theoretical model that we think we have some evidence to support,” says Strong. “It is possible that a normal function of the neurofilament is to bind up residual oxidative species that are producing the damage, and that the reason the aggregate forms is there is a deficiency of this particular protein. Forty per cent of its level is sufficient to produce an ALS-like syndrome in a transgenic mouse.”
Another piece was recently added to the puzzle when Strong compared his observations of ALS motor neurons with whole ALS spinal cord tissue, containing not only motor neurons, but all spinal neurons. The neurofilament subunits were low overall in the isolated motor neurons, but surprisingly high in the whole tissue samples. “That really suggested that there was some regulation of how these things were controlled,” says Strong. Further research revealed “destabilizing proteins,” which affect the levels of the RNA from which the individual proteins are made. The researchers now propose that in the face of stress, neurofilament proteins are needed and their levels can be controlled via the destabilizing proteins. “If the normal response is to have the destabilizers expressed,” says Strong, “then when you stress the neuron, the destabilizer expression should be dropped, allowing an oxidative-protective pathway. But in ALS, we are arguing that that does not occur.”
Strong believes that process may begin a cascade of events that leads to the death of the motor neuron. “Once that injury occurs, this injured neuron will recruit inflammatory cells called microglial cells.” The immune response can take two paths: it can be beneficial and aid in repair, or it can be incredibly harmful and actually kill the cells. In addition, the injured motor neurons could trigger their own death. The disease process could begin in a small group of cells, or even just one cell, Strong explains, and spread from there. In fact, he has shown it is possible to carry the cascade from one cell culture to another simply by transferring the medium of diseased cells to cultured microglial cells, and then to healthy motor neurons.
Strong sees between 120 and 150 new cases of ALS each year, with patients from Newfoundland to the mid-west. He believes an effective ALS therapy will require attacking the complex disease process at many levels. “It will almost certainly require multi-level pharmacotherapy. The challenge will be to find such therapy before another century passes in our understanding of the disease.”
| Posted On: Monday, April 19, 2004 Modified: Monday, April 19, 2004 Category: Researchers Posted By: |