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The cause of ALS is not known. However, it is likely that ALS is a complex multi-system disease with several mechanisms that cause the death of motor neurons. Any one of these mechanisms or a combination of several may be responsible for the disease. Furthermore, there are likely to be genes and hereditary factors that will modify the disease and susceptibility. These mechanisms and the pathways influenced by modifying genes provide targets for therapeutic strategies. The most important mechanisms are outlined below.
To date, one of the most robust theories of pathogenesis of ALS is excito-toxicity of glutamate. Glutamate is a common chemical in the nervous system used for signaling between neurons. While it is important for normal nerve cell function, it is toxic in excess. There is evidence of increased glutamate in ALS patients and in ALS mice and this in turn may be responsible for nerve cell death. The increased glutamate may result from either abnormal transport of glutamate out of the nerve cell environment or increased release of glutamate from nerve cells. To date, there is some evidence that the transporter responsible for removing glutamate from the nervous system may be altered and/or the process for making the transport protein damaged.
Free radicals are molecules with unpaired electrons. These molecules are unstable and liable to damage cellular structures including proteins and lipids (fats) within nerve cells. Free radicals are a normal part of cellular life and cells are usually able to neutralize them and keep their numbers in check. However, in ALS, free radicals build to toxic levels and damage cells, through an attack process called oxidative stress. It is of interest that 20% of Familial ALS patients have mutations in SOD1, an enzyme that detoxifies oxygen free radicals. There is evidence that there are higher levels of protein carbonyl groups (caused by oxidative stress to proteins) and oxidized nucleic acids in brain tissue from patients with sporadic ALS.
Free radicals are also produced in the powerhouse of the cell called the mitochondria. Mitochondria and its genetic material are especially sensitive to the oxidative damage from free radicals and may be one of the earliest sites of damage in ALS and in familial ALS. This in turn results in lower energy production by the nerve cell and less ability to do its job.
Ten percent of ALS is inherited and 20% of these patients carry a mutation in the Superoxide Dismutase Gene (SOD1). In addition there may be other genetic factors that play a role in the cause of ALS. One such factor is the level of the protein VEGF (vascular endothelial growth factor) that is made depending on the structure of a persons’ VEGF gene. Another genetic factor recently implicated is the gene for the iron processing protein HFe. Other factors include how the genetic message (mRNA) for the glutamate transport protein is processed and the presence of mutations in the gene for the structural protein called neurofilament. The possible genetic contribution to the development of ALS is an active research area.
ALS may be due to an early death of motor neurons or a premature initiation of programmed cell death or suicide (called apoptosis).
Neurofilaments provide a scaffold structure to maintain the long process (called the axon) that extends from the cell body of nerve cells out to the muscle or down the spinal cord. These filaments also provide the railroad tracks to transport important molecules up and down the axon. It has been shown that neurofilaments accumulate in the nerve cell body and processes (called axons) in ALS as well as animal models.
There is a higher incidence of immune disorders and abnormal immune system made proteins (including monoclonal gammopathies and anti-GM1 antibodies that were discussed above) in people with ALS. Immune attacks on the nerve cells could trigger increased intracellular calcium and motor neuron degeneration. In addition, it has been demonstrated in both the mouse model of ALS that carries the mutated SOD1 gene and in people with ALS that there is inflammation in the brain. Special inflammatory cells in the brain called microglia are activated and there is an increase in proteins such as COX 2 that produce a state of inflammation by increasing the production of inflammatory mediators. These mediators are called cytokines and some are protective while others can damage cells. The balance of the types of cytokines produced will determine if the overall effect of inflammation is good or bad!
This is the clumping of proteins that are misshapen either because of damage from ongoing cell processes or through the inheritance of an abnormal structure in genetic disorders. There have been abnormal clumps of protein identified in mice with ALS that carry the mutated gene for SOD 1 as well as other animal models of motor diseases. These clumps of protein may interfere with normal motor nerve cell functions leading to cell death.
The idea that viral illness may play a role in ALS comes from several lines of evidence. First, polio virus causes a motor system disease that affects the lower motor neurons. Secondly, genetic material from a type of virus called echovirus was found in the spinal cords of ALS patients. Finally, HIV (human immunodeficiency) virus can cause an ALS-like syndrome that improves with antiviral drugs.
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