Motor neuron disease

Question 1

What is motor neuron disease?

Answer 1

It is a collective term for a group of multiple diseases that affect motor neurons. The most common one being Amyotrophic lateral sclerosis

Question 2

Do motor neuron diseases affect all neurons?

Answer 2

Nope. They affect only the lower motor neurons, that directly innervate the muscles.

Question 3

What is the difference between upper motor and lower motor neurons?

Answer 3

Upper motor neurons originate in the brainstem and so do not directly innervate peripheral muscles. Lower motor neurons do.

Question 4

What are the initial symptoms of motor neuron disease?

Answer 4

Difficulty swallowing, muscle weakening, tripping and clumsiness.

Question 5

As the disease progresses, what are the late stage symptoms?

Answer 5

Paralysis and respiratory problems. Most sufferers will be killed because of the respiratory problems.

Question 6

Are there any diagnostic tools or tests for motor neuron disease?

Answer 6

No- not at the moment. They simply use a process of elimination to check that the symptoms are not from other diseases.

Question 7

What is the current treatment option for motor neuron disease?

Answer 7

A drug called Riluzole (Rilutek). The mechanism as to how it works will be explained later.

Question 8

What are the genetic factors that can cause motor neuron disease?

Answer 8

Cu/Znsuperoxidedismutase(SOD1)
‐ TDP‐43
‐ Optineurin
‐ Angiogenin
‐ C9ORF72

Question 9

What are the environmental factors that can cause motor neuron disease?

Answer 9

Headtrauma
‐ Militaryserve
‐ Toxins(β‐
methylamino‐L‐alanine;BMAA)

Question 10

Glutamate excitotoxicity is one a known cause of motor neuron degeneration. Describe this process.

Answer 10

Glutamate excitotoxicity is when the motor neurons become damaged by excessive stimulation from the neurotransmitter glutamate.

Question 11

What is the evidence to suggest that glutamate excitotoxicity is responsible for motor neuron degeneration?

Answer 11

1. Decreased amount of GLT-1 glutamate transporter on neurons.
2. Increased glutamate concentration in the CSF

Question 12

What is the relationship between Riluzole and glutamate?

Answer 12

Riluzole is known to reduce the glutamate levels in the CSF, to prevent overstimulation of nerves and stop excitotoxicity.

Question 13

What is the evidence against glutamate excitotoxicity as the cause of motor neuron degeneration?

Answer 13

1. Other excitotoxicity specific drugs don’t work with MND.
2. Riluzole does not work to reduce excitotoxicity in ‘in vitro’ trials. (Testing in the lab, with specimens removed from the body).

Question 14

What is SOD1?

Answer 14

SOD1 is the shortened name for the enzyme called superoxide dismutase. This enzyme is an anti-oxidant produced in all cells of the body. It detoxifies radical species using copper and zinc ions.

Question 15

Mutations to the SOD1 gene result in mutated SOD1 enzyme. What is the mutation?

Answer 15

The mutations sees superoxide dismutase being produced that doesn’t have any metal ions on it. This is called ‘Metal deficient’ SOD1.

Question 16

Does mutated, metal-deficient SOD1 work the same as normal SOD1?

Answer 16

No. Metal-deficient SOD1 is toxic whilst normal SOD1 is not.

Question 17

What does toxic SOD1 do to motor neurons to induce pathology?

Answer 17

Metal-deficient SOD1 induces apoptosis of motor neurons.

Question 18

How exactly does toxic SOD1 induce apoptosis of only motor neurons, and not just every cell in the body where it is found?

Answer 18

1. Neurons have very high demand for energy. They rely solely on their mitochondria to produce it for them.
2. The neurons have very high amounts of mitochondria in them.
3. SOD1 is toxic to the mitochondria and causes mitochondrial dysfunction which leads to induction of apoptotic pathways.

Question 19

Misfolded SOD1 can also induce MND. How does it become misfolded?

Answer 19

Exposure to rare cyanobacteria can cause the SOD1 protein to misfold and thus mutate, leading to MND.

Question 20

How can oxidative stress cause MND?

Answer 20

Oxidative stress is when there is an increased number of free radical species, that can oxidise and damage neurological structures and SOD1.