By now, we have all either seen, been nominated, or actively participated in the ALS ice bucket challenge. We know that the money is going to a good cause, either to fund ALS research or help those who are affected by this awful disease. We know influential people who have had the disease such as Steven Hawking and Lou Gehrig. But how much do we know about the disease itself? Lets break it down into more bite sized pieces.
Description:
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by muscle weakness due to the breakdown and death of motor neurons (the cells that deliver signals from the brain to the muscles). This leads to loss of neuronal function and ultimately to paralysis. (Additional information can be found at the ALS website, www.alsa.org)
Cause:
The primary cause of necrosis (death) of the motor neurons is a phenomenon called excitotoxicity. Excitotoxicity in ALS, occurs when there is too much of a neurotransmitter called glutamate in the synapse (the junction between two nerve cells). This causes overstimulation of the cell, leading to problems with functional pathways further down the nerve cell. The primary receptor to glutamate that has been studied is called NMDAR. It is different than other receptors for glutamate because it requires co-agonists, or other substances in addition to glutamate, to trigger a response by NMDAR.
Current Treatment:
There is only one drug currently on the market that is used to treat ALS. The drug Riluzole acts by suppressing the release of glutamate and the receptors that respond to glutamate in the synapse. This method attempts to reduce the excitotoxicity that is caused by ALS in the synapse.
New Findings (co-agonists):
(Glycine/D-serine)
Both Glycine and D-serine are co-agonists which affect the NMDAR receptor. Glycine has been shown to promote the release of glutamate which can increase the risk of excitotoxicity in a neuron affected by ALS. On the other hand, high levels of D-serine have been linked with NMDA toxicity. This occurs because the over activation of NMDA causes a pathway that leads to cell death (ERK1/2-/p38)
(Zinc)
Zinc performs several important functions within the cell. A vast majority of zinc found in the body is tightly bound to zinc dependent enzymes. Missense mutations within these zinc dependent enzymes have been linked to 20-25% of ALS cases. It has been found that those zinc deficient enzymes can then lead to ALS.
(Polyamines)
Polyamines, such as spermine and spermidine, have been found to be allosteric modulators of the NMDAR receptor (they bind to the receptor in a site different that the normal active site and by doing so, change the shape and function of the receptor). It has been found that these polyamines enhance the activity of NMDAR, thus causing a pathway which leads to cell death. Unlike many other neurotransmitters, polyamines are found throughout the body and not just in the neurons. In patients with ALS, polyamines have been found in higher concentrations within red blood cells.
It is clear that there is no one cause ALS, and the pathways that lead to its symptoms are very complex and for the most part are not fully understood. Although fund raisers such as the ALS ice bucket challenge might seem trivial, they take steps toward finding an ultimate cure for the disease, and offer the families of those who are affected, with much needed support.
ALS, More than a Social Media Phenomenon
