ALS Etiology

Pathology and Etiology

Amyotrophic Lateral Sclerosis (ALS) is a relatively elusive disease. ALS is a disease that affects the large upper and lower motor neurons of the motor cortex, brain stem, and spinal cord . The destruction of the upper and lower motor neurons causes progressive paralysis. Even with research of ALS beginning in 1869, and becoming more widely known in 1939 (About ALS), the cause is still being heavily researched. Luckily, scientists have come across quite a few theories as to the cause of ALS. The validity of many of the theories are still being tested, but a few of them have found their way to being a staple in ALS etiology. Sporadic ALS (sALS) accounts for 90% of diagnosed cases. The exact cause of sALS is unknown,

EEA2 transporters are primarily found in the central nervous system (CNS) and are responsible for moving glutamate away from synapses shortly after it is released; the swift removal of glutamate is meant to prevent prolonged excitation of nerve cells (Foran & Trotti, 2009). With the dysfunction of EEA2 transporters, glutamate over excites the postynaptic membranes of nearby nerve cells—the over abundance of the excitatory neurotransmitter, as well as the prolonged contact, causes an increase in calcium (Ca2+) permeability of surrounding nerve cells. The increase of Ca2+ permeability also causes the release of intracellular Ca2+ stores. Along with the influx of intracellular Ca2+, sodium (Na+) follows the Ca2+ into the cell, causing further stimulation. As a result of the increased intracellular levels of Ca2+ and Na+, potassium (K+) leaves the cell—the resulting effect is cell swelling and death of the neuron. Glutamate isn't the only factor that can play into the fatal disease though, oxidative stress can also be a contributing

ROS are produced by metabolic processes in the body (Oxidative Stress, 2014). In aerobic metabolism the mitochondria uses about 90% of oxygen—this means that the mitochondria are most responsible for the production of ROS (Barber, S. C., Meade, R. J., & Shaw, P. J.,2006). The over abundance of intracellular Ca2+ levels in the neuron is closely linked with oxidative stress. Excessive intracellular Ca2+ are not only responsible for the swelling and death of neurons, but it also is one of the causes of the production of ROS. When ROS are over produced they cause the inhibition of glutamate uptake through EEA2 transporters, hence the vicious cycle of excitotoxicity. When the intracellular levels of Ca2+ increase, it is the job of mitochondria to take in Ca2+; the intake of Ca2+ by the mitochondria causes increased ROS production. ROS cause damage to DNA and protein, which causes the destruction of neurons (Barber, S. C., Meade, R. J., & Shaw, P. J. 2006.) Although studies have shown the link between sALS and oxidative stress, further research is being done to prove or disprove this