Lecture 21 - Motor Neuron Disease

Question 1

What is motor neuron disease?
1)
2)
3)
4)

Answer 1

1) A collection of diseases
2) Most common is amyotrophic lateral sclerosis
3) Progressive, fatal
4) Common feature is that all affect motor neurons

Question 2

Most common form of motor neuron disease

Answer 2

Amyotrophic lateral sclerosis

Question 3

Upper motor neurons

Answer 3

Originate in the brain, brainstem

Don’t directly innervate muscle

Question 4

Lower motor neurons

Answer 4

Originate in the spinal cord

Directly innervate muscles

Question 5

Symptoms of motor neuron disease
1)
2)
3)
4)
5)
6)
7)

Answer 5

1) Muscle twitching
2) Muscle weakness
3) Difficulty speaking
4) Difficulty swallowing
5) Tripping, stumbling, dropping things
6) Progressive paralysis
7) Decreased respiratory function

Question 6

Most common cause of death in MND

Answer 6

Respiratory failure

Question 7

Peak age of onset of MND

Answer 7

45-60

Question 8

Effect on muscles of MND

Answer 8

Muscle atrophy

Question 9

MND effect on sensory nerves

Answer 9

Sensory nerves are spared

Question 10

Diagnosis of MND
1)
2)
3)

Answer 10

1) No diagnostic test
2) Purely clinical
3) Diagnosis often comes about as a result of a process of elimination

Question 11

Prognosis of MND
1)
2)

Answer 11

1) Confined to wheelchair within 1-2 years

2) Death within 3-5 years

Question 12

Only approved MND therapy

Answer 12

Riluzole (‘Rilutek’)

Moderate clinical efficacy

Question 13

Genetic factors in MND
1)
2)
3)
4)
5)

Answer 13

1) Copper/Zinc superoxide dismutase
2) TDP43
3) Optineurin
4) Angiogenin
5) C9ORF72

Question 14

Possible environmental factors in MND
1)
2)
3)

Answer 14

1) Head trauma
2) Military service
3) Chemical toxins

Question 15

Number of cases of MND with a sporadic basis

Answer 15

Over 90%

Question 16

Effect of riluzole

Answer 16

Increases GLT1 uptake of glutamate into astrocyte

Question 17

Mutant gene associated with familial MND

Answer 17

Copper/zinc superoxide dismutase (SOD1)

Question 18

Copper/zinc superoxide dismutase 
1)
2)
3)
4)
5)
6)

Answer 18

1) Expressed in every cell in the body
2) Major antioxidant enzyme
3) Detoxifies toxic oxygen radicals
4) ~150aa
5) Binds one copper, one zinc atom
6) Substitution mutations in SOD1 can cause familial MND

Question 19

Reaction involving SOD1

Answer 19

SOD1 + O2-* + 2H+ –> SOD1 + H2O2

Question 20

Possible gains of function in mutant SOD1
1)
2)
3)
4)

Answer 20

1) Pro-oxidant gain of function
2) Protein misfolding
3) Protein aggregation
4) Mitochondrial dysfunction

Question 21

Inheritance pattern of most familial MND

Answer 21

Autosomal dominant

Question 22

Old theory of development of familial MND

Answer 22

More mutant SOD1 leads to more severe phenotype

Question 23

What is 'latency to fall'?
1)
2)
3)
4)

Answer 23

1) Mice are placed on a rotating rod.
2) Latency to fall is the time taken for a mouse to fall off
3) Normal mice take ~150 seconds throughout their lives
4) Mice with MND rapidly lose the ability to stay on the rod

Question 24

New theory of development of familial MND

Answer 24

More metal-deficient SOD1 leads to more severe phenotype

Question 25

Possible states of SOD1
1)
2)
3)

Answer 25

1) Apo (no Zn or Cu)
2) Metal-deficient (only Zn or Cu, not both)
3) Holo (both Zn and Cu)

Question 26

Effect of drug being trialled

Answer 26

Increase the amount of Holo SOD1, reduces the amount of metal-deficient SOD1, possibly by converting metal-deficient to Holo

Question 27

Toxic form of SOD1

Answer 27

Metal-deficient

Question 28

Why is Apo SOD1 not toxic?

Answer 28

It is broken down extremely rapidly.

Question 29

Possible diagnostic tool for MND
1)
2)
3)
4)
5)

Answer 29

1) Give patient radioactive isotope of Cu
2) SOD1 is very stable, so will retain radioactive Cu
3) If there is no Cu deficiency in spinal SOD1 (as in a healthy person), there will be no uptake of radioactive Cu there.
4) If someone has MND, there will be a deficiency in spinal Cu in SOD1, and radioactive Cu will be present in spinal cord.
5) This can be detected with a PET scan