Multiple Problems May Cause Motor Neurons to Die
Four of the most frequently cited theories to explain why motor neurons die in ALS are illustrated here. Scientists believe these processes may work together, with a combination of problems underlying motor neuron loss.
1. Glutamate Excitotoxicity
This theory proposes that nerve cell death occurs in ALS because the cells become overexposed to a naturally occurring brain chemical called glutamate when it isn't removed after nerve cells signal to one another. This overexposure causes the motor neurons to take in too much calcium, leading to the disruption of many cellular functions and, eventually, to cell death. The drug riluzole is thought to work by reducing the amount of glutamate released when nerve cells signal.
2. Oxidative Stress
Some investigators think motor neurons die in ALS when they're overwhelmed by highly charged destructive molecules called free radicals. Free radicals damage components of the cells' membranes, proteins or genetic material by "oxidizing" them — the same chemical reaction that causes iron to rust. These free radicals may be generated when the enzyme superoxide dismutase malfunctions (either because of a genetic mutation or because of the chemical environment of the nerve cells), or they may be generated as a result of glutamate excitotoxicity, or for some other reason. Coenzyme Q10 and vitamin E are examples of over-the-counter "antioxidants" that help neutralize free radicals.
3. Protein Aggregates
Many researchers have noted the presence of abnormal aggregates, or clumps, of proteins in the motor neurons of people with both familial and sporadic ALS, as well as in those of animals engineered to have a mutation in the superoxide dismutase gene. Some researchers suggest that these protein aggregates are themselves toxic to nerve cells, while others propose they're not the main cause of nerve cell death. The aggregates may arise when the cells' system for repairing incorrectly folded proteins becomes overtaxed by environmental problems or age-related changes.
4. Axonal Strangulation
This theory concerns the collection of clumps of proteins called neurofilaments that normally provide structural support for the motor nerve cell's longest component, the axon. When the neurofilaments of the axon become tangled, the transport of important nutrients from the cell body to the far reaches of the axon may be impeded. Some researchers think this blockage causes the motor nerve cell to die slowly of "strangulation." It isn't clear why the neurofilaments form clumps, but there's some evidence that this occurs when the ratio of one type of neurofilament to another becomes imbalanced.
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