Question 1: In the incurable neurodegenerative disease amyotrophi...

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Question 1:
In the incurable neurodegenerative disease amyotrophic lateral sclerosis (ALS), the neurons in the brain and spinal cord that control skeletal muscles gradually die, causing muscle weakness and eventually death. These neurons have very long axons. One gene that is often mutated in inherited cases of ALS is copper/zinc superoxide dismutase 1 (SOD1).

In the paper below, the investigators wanted to know whether there were axonal transport deficits in the mice that were expressing mutant versions of SOD1. These mutant alleles cause ALS in humans. The mice were the SOD1G37R and SOD1G85R mice:

Williamson & Cleveland 1999, Slowing of axonal transport is a very early event in the toxicity of ALS–linked SOD1 mutants to motor neurons, Nat. Neurosci 2, 50–56. https://www.nature.com/articles/nn0199_50

a. ALS affects the motor neurons. Are these neurons projection neurons or interneurons, and how do you know?
b. If a deficit in axonal transport contributes to ALS, does it make sense that the type of neuron you picked in part a (projection neuron or interneuron) is affected? Justify your reasoning.
c. Motor neuron axons are very thick in addition to being long. What might be a reason that they evolved to be so thick? In your explanation, embed at least one equation from physics.
d. To measure the rate of slow axonal transport, the investigator labeled various proteins with radioactivity, waited until they could be transported, and then cut up the axons into segments and looked for how far the radioactivity traveled. They did the same for fast axonal transport, except on a different timescale. For the SOD1G37R mice, the results of these experiments are in Figures 1e/f and 7.

Say that Model 1 is “axonal transport is normal” and Model 2 is “all axonal transport is disturbed.” Based on these Figures, what do you conclude about axonal transport in this ALS mouse model? In your justification:
- State and justify whether the results of these experiments better match Model 1, Model 2, or neither model.
- Refer to specific features of the Figures, like their peaks

e. In Figure 5, the investigators did immunohistochemical staining for βIII–tubulin. For this experiment, could they theoretically have used a genetically-encoded βIII–tubulin tagged with GFP instead? Justify your response.
f. A later paper found that disrupting only dynein in mutant mice could cause a disease that is very similar to ALS (LaMonte et al, 2002). Do the second paper’s results support your conclusions from Figures 1e/f, 7, and 5 from the Williamson & Cleveland 1999 paper? Justify your reasoning.

Question 2
There is a part of the brain called the thalamus where nearly all the information from your senses goes before it reaches the cortex, which creates conscious perception. In thalamic neurons, application of the general anesthetic halothane causes the resting membrane potential to decrease.

You want to study this phenomenon, so you take some thalamic neurons and put them in a dish. You do a few experiments and notice a few things:
● Applying halothane causes the resting membrane potential to decrease.
● In one experiment, blockers of voltage-gated sodium channels and voltage-gated potassium channels were added, and sodium and calcium were removed from the cell’s extracellular and intracellular solutions. Under these conditions, there was a current with a reversal potential of -92mV, very close to the reversal potential of potassium at -94mV.
● That current becomes much greater in amplitude when halothane is applied.

A. Based on the information above, what is halothane likely doing to alter the resting membrane potential, and why would this lower the resting membrane potential? Justify your response with reasoning.

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These solutions may offer step-by-step problem-solving explanations or good writing examples that include modern styles of formatting and construction of bibliographies out of text citations and references. Students may use these solutions for personal skill-building and practice. Unethical use is strictly forbidden.

a. ALS affects the motor neurons. Are these neurons projection neurons or interneurons, and how do you know?

Since ALS affects both corticospinal motor neurons in the cortex as well as in the spinal cord, it can be said that these neurons are projection neurons.

b. If a deficit in axonal transport contributes to ALS, does it make sense that the type of neuron you picked in part a (projection neuron or interneuron) is affected? Justify your reasoning.

There are studies showing that deregulation of interneurons activity can lead to induced hyperexcitability in motor neurons and accumulation of proteins in motor neurons. Although the mechanism is unknown, the Williamson and Cleveland article showed that novel property of mutant versions of SOD1 can disturbed axon transport in motor neurons. The disturbances in axon transport and accumulation of proteins have cytotoxic effects, axon swelling and finally death of those motor (projection) neurons.

c. Motor neuron axons are very thick in addition to being long. What might be a reason that they evolved to be so thick? In your explanation, embed at least one equation from physics.

The reason why axons evolved to be thick and long is because the larger the diameter of axon, the resistance of axon cytoplasm is lower and the faster the transmission of action potential. From the Hodgkin-Huxley equations for propagation velocity (speed of impulse propagation, ν) we can see that the thicker the axon, the lower the cytoplasmic resistance and the higher the velocity....

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