Amyotrophic Lateral Sclerosis (ALS)

Describe biotechnology developed to assist respiratory function in a person with ALS

Having ALS effect your respiratory function decreases your life expectancy because of the risk for noumena, some need a mechanical ventilator to survive but it is risky. Place two electrodes on each diaphragm and an electronic device stimulates the muscles and nerves allowing muscles to contract and air to enter the lungs.

Describe the TDP-43 and C9orf72 gene mutation theory contributing to motor neuron death in ALS.

These genes mutations cause an accumulation of proteins in the neuron leading to death of the neuron. 40-50% have a mutation with the C9orf72 gene.

Describe the basic pathology of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) in terms of the selective loss of motor neurons from either the cerebral cortex, anterior horn of the spinal cord, and/or brainstem motor nuclei of cranial nerves.

This disease is a degeneration of upper Motor neurons (arising in cerebral cortex) and lower motor neurons (arising in anterior horn cells of the spinal cord or lower brain stem)

Describe the biological process of antisense oligonucleotide (ASO) therapy and identify the goal of ASO therapy for ALS.

This therapy uses probes. These strings of nucleic acids form bonds to the mutated form of RNA made from the mutated gene. ASO molecule will be injected into the individuals cerebral spinal fluid and binds to mRNA which is responsible for the death of motor neuron. Once they bind molecules work together to degrade the mutated form of the gene.

Describe the superoxide dismutase gene mutation theory causing ALS

normally, super oxide dismutase enzyme is a free radical scavenger. Its uncontrolled free radicals have the capability to destroy cell membranes leading to death.

Describe the neurofilament theory causing ALS

the neurofilament protein creates a structural protein known as a cytoskeleton. This is inside the neuron and helps maintain the shape and integrity and organization inside of the neuron. However, a downside of this is that it can lead to a creating an abnormal cytoskeleton resulting in early death

Describe the connections and routes of nerve fibers forming the corticospinal tract from the primary motor cortex (in the frontal lobe) through the brain and spinal cord to skeletal muscle. Name all relevant regions of the spinal cord and brain these fiber bundles form or pass through. Distinguish between upper motor neurons and lower motor neurons.

there is a group of neurons in the precentral gyrus of the frontal lobe/primary motor cortex that are selectively vulnerable to undergoing degeneration in this disease, which eventually leads to the person not being able to have control of their voluntary skeletal muscle activity leading to paralysis. When motor neurons die, the axons that descend down into the spinal cord, will eventually be removed from the spinal cord and they were no longer be any type of communication from the motor neurons.

Describe some of the proposed theories that may underlie the pathogenesis of some of the familial form of ALS including: glutamate excitotoxicity, neurofilament gene mutation, superoxide dismutase gene mutation, TDP43 gene mutation, and C9orf72 gene mutation.

Glutamate excitotoxicity is a gene that works to remove glutamate from the synaptic cleft. Glutamate is released from the presynaptic cleft binding to its receptor on the post synaptic cleft. Now we have to get rid of the glutamate, to inactive it the transporters will remove the neurotransmitters from the area and can take it back up to the presynaptic axon terminal or the surrounding glial cells. Superoxide dismutase gene mutation produces a free radical scavenger molecule

describe the mechanism of action of Radicava.

Radicava is the second drug approved by FDA described to work as a free-radical scavenger

describe the mechanism of action of Riluzole.

Riluzole is a drug that blocks the release of glutamate, treating ALS symptoms and side effects

Describe symptoms and clinical manifestations of ALS highlighting the fact this is primarily a loss of motor function (except motor to eyes) (sensory functions remain relatively intact; i.e. visual pathways and others).

Sensory and cognitive functions remain intact, however, noticeable progressive muscular weakness and muscle atrophy.

Describe the glutamate excitotoxicity theory causing ALS

The glutamate excitotoxicity theory is when there is a defect in the transport protein in removing glutamate from the presynaptic cleft. Which allows it to being for a longer amount of time. Glutamate is known to excite the post synaptic cell, so when there is too much glutamate overstimulating the post synaptic cell can cause the cell to die from too much excitement on the post synaptic cleft-excitotoxicity

Describe the typical appearance of a silver-stained cross-section of spinal cord from a person with ALS.

absence of myelin due to no axon. The axon of the lateral corticosteroid tracts have died. Death motor neurons, loss of axons and loss of myelin is what we see when we look at the cross-section. There is still tissue, but it is filled in with gliotic scar tissue that forms in the central nervous system. (sclerosis=scar)