It has been more than a century since the first complete description of ALS by Dr. Charcot. Since then, although theories with regard to the cause of ALS have been numerous, very few have found validation through scientific study. While several current hypotheses for the cause of ALS exist, researchers now believe that ALS can be a disease of multiple causes sharing a common pathway leading to the destruction of the motor neurons. By understanding the mechanisms by which this common pathway is triggered, we will ultimately understand ALS. Through such understanding, desperately needed therapeutic options will be developed. In this section, we will highlight these hypotheses and their relevance to our understanding of ALS.

Environmental Hypothesis
The exceedingly high incidence rates of ALS observed during the mid 40s and 50s on the island of Guam in the Western Pacific and the Kii Peninsula of Japan have been attributed to dietary toxins. Individuals living in these regions were found to be calcium-deficient and because of the hyperparathyroid state induced as a normal response to this deficiency, coupled with significantly elevated soil and water aluminium levels, a state of aluminium toxicity was induced. That aluminium exposure in this specific population could bring about ALS has been subsequently demonstrated in animal models utilizing aluminium supplementation of calcium and magnesium-deficient diets to produce a syndrome very similar to ALS.

In an alternate hypothesis, the ingestion of the false sago palm cycad circinalis or its utilization as a medicinal poultice has also been incriminated as an environmental toxin that may have brought about the abnormally high rates of ALS in the Western Pacific. Regardless, with dietary and medicinal changes brought about by the Westernization of this culture, the incidence rates of ALS in the Western Pacific have now declined to levels approaching North American rates. The importance of these observations has been to demonstrate that, in a susceptible population, certain dietary toxins can induce ALS. Although to date no evidence for such a process has been found for sporadic ALS, worldwide epidemiological studies consistently point towards environmental triggers as being important.

Inherited Variants of ALS
In 5 to 10% of people with ALS the disease is inherited. Approximately 15% of patients with dominant familial ALS have abnormalities in a key cellular enzyme termed the copper/zinc superoxide dismutase (SOD-1). Although initially postulated that this abnormality alone would be sufficient to cause ALS, it is becoming increasingly clear that abnormalities in SOD-1 function alone may be insufficient to produce ALS in all individuals carrying this genetic mutation. In addition to SOD-1 abnormalities, genetic abnormalities in the neurofilament genes have been discovered, as have impairments in cell surface receptors in specific forms of motor neuron disease that can mimic ALS (for example Kennedy's syndrome).

Free Radical Hypothesis
All cells generate toxic metabolites (think of these as the "exhaust” from your car and the consequences to yourself and your passengers should your car not be properly vented). In the cell, these "exhausts” ("free radicals”) are a destructive form of oxygen that can also be used by the cell under normal circumstances to fight disease. However, an overproduction of free oxygen radicals can result in cell damage and death. As might be expected, several defenses against such a process exist. A major one is the superoxide dismutase enzyme (SOD-1). As discussed above, mutations in the SOD-1 gene have been postulated to allow excessive free radical production and the destruction of the neuron. Canadian researchers have documented the existence of excessive levels of proteins damaged by free oxygen radicals within neurons in ALS, suggesting that either the neuron synthesizes excessive levels of free radicals, or that it is incapable of "venting” those that are normally produced.

Immunological Hypothesis
There has, to date, been very little evidence to suggest that ALS can be due to a primary abnormality of the immune system as we might classically think of it. However, the nervous system possesses its own capacity to mount an immune response to the injury of neurons. The response can be either advantageous in removing the debris from damaged regions, or it can be harmful in inducing even further damage. Recently, investigators have become increasingly aware of the extent of the immunological response of the central nervous system in ALS.

Researchers in Vancouver have proposed that ALS, similar to other neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, possesses a prominent local immune response, mediated by microglial cells, that adds further to the injury of motor neurons and may be responsible for the disease continuing.

Hypothesis of Neurotrophic Factor Deficiency
These important factors for the growth and maintenance of motor neurons in humans have been shown to enhance motor neuron survival in mice with a variety of motor neuron disorders. Although it is not clear how deficiencies of neurotrophic factors may affect human motor neurons, several attempts have been made to determine whether neurotrophic factors can slow the rate of progression of ALS by first testing these agents in animal models of the disease. Although initial clinical trials with ciliary neurotrophic factor (CNTF) or brain-derived neurotrophic factor (BDNF) failed to alter the course of ALS, this may have been due to a failure of these neurotrophic factors to reach the damaged motor neurons. Current clinical trials in Edmonton, London, and Montreal are attempting to circumvent this problem, by using either direct application of the neurotrophic agent to the spinal fluid, or by administering large quantities of the agent systemically (for example, by injections like those given for diabetes). In addition to these studies, novel neurotrophic factors continue to be described that will impact on the survival of motor neurons (for example, insulin-like growth factor [IGF-1], cardiac derived neurotrophic factor, etc). Combination studies are also being developed in Hamilton.

Hypothesis of altered neurofilament metabolism
A particular hallmark of the damage to motor neurons in ALS is the accumulation of neurofilaments – key neuronal proteins believed to be responsible for maintaining the normal neuronal structure and shape. Through research funded by the ALS Society of Canada, it has become clear that abnormalities in the metabolism of neurofilaments can be critical to the production of a disease bearing all of the hallmarks of ALS. Such studies have been undertaken through the use of transgenic models of altered neurofilament expression and through aluminium-induced neurotoxicity. Using mouse models in which individual neurofilament proteins have been either removed completely, or forced to be present in excess, researchers in Montreal have shown that a simple alteration in the amount of neurofilament within the neuron can lead to an ALS-like syndrome. Others in Montreal have shown that interfering with the way in which neurofilaments interact with each other in cell cultures produces aggregates of neurofilament similar to those observed in ALS. In London, researchers have shown that changing the interactions between neurofilaments and other key proteins can similarly lead to ALS.

Excitatory Amino Acid Toxicity Hypothesis
Abnormalities in the handling of excitatory amino acids by the nervous system, particularly glutamate, may be critical to the occurrence of ALS. Through damage to the normal "transporter” mechanisms by which glutamate is removed from the nervous system, excessive glutamate accumulates. As demonstrated by researchers in Vancouver, this excessive glutamate can directly damage motor neurons.