Neurophysiology of ALS
Amyotrophic Lateral Sclerosis is a disorder of the Central nervous system's motor neurons. This includes both upper and lower motor neurons. Motor neurons, are those neurons whose effectors are ultimately muscle cells. They are responsible for enervation of the musculature. As such, ALS victims retain their full intellectual capacity and intelligence, as motor neurons have little effect on the cognitive aspect of the nervous system.
Neurons regularly release a synaptic vessicle to muscles, even without prior stimulation. This single vessicle causes what is known as a mepp, or miniature end-plate potential. These mepps occur at regular intervals even when there is no stimulation. The mepps appear to be trophic in nature, in that muscles in which mepps where blocked atrophied. This means that the mepps correspond to a signal sent from the nervous system to the muscle saying "I'm here everything is fine, and we need this muscle". When mepps are not present the muscle behaves as if it is not ennervated and begins to atrophy. Mepps correspond to a single vessicle of neurotransmitter release, also referred to as the quanta of synaptic transmission.
In ALS the motor neurons undergo shrinkage accompanied by the accumulation of lipofuscin. Lipofuscin is a pigment that is harmless, but is indicative of neuronal age. Older neurons contain more, than younger ones do. ALS patients show a premature accumulation of this pigment, possibly indicating premature neuronal aging. The neuronal shrinkage is caused by the diseases effects on the neurons cytoskeleton (a network of neurofibrils and filaments, microtubules and actin filaments). The cytoskeleton is altered and focal enlargements, or spheroids, caused by accumulations of neurofilaments are common.
As the motor neurons shrink, they ennervate less and less musculature,and those muscles atrophy. This is the basis of the term amyotrophy. Initially ALS manifests itself in those neurons that ennervate more lateral or distal muscles. Generally this disorder first starts in the hands and rarely in the feet. The loss of the motor neurons then progress from lateral to more medial muscles. Thus hands then forearm and finally whole arm. Consequently this is also the organization of the nerve tracts in the spinal column, with the more distal appendages represented more laterally in the anterior and dorsal horns of the spinal cord.
The exact causes of the neural degeneration is unknown, while 5-10 percent can be attributed to a certain inherited dominant autosomal trait. There are multiple genes in which if mutated may cause ALS, one of these genes encodes for an enzyme called superoxide dismutase. This type of inherited ALS, is often called FALS. Some researchers have further suggested that the neurotransmitter glutamate is may lead to neuronal cell death. High concentrations of glutamate is toxic to the cell. It is interesting to note that superoxide dismutase is an enzyme used to detoxify a superoxide anion free radical. The combination of these two pieces of information may suggest that glutamate toxicity and ALS are results from free radical accumulations in the motor neurons.
