Lecture 21 - Motor Neuron Disease Flashcards Preview

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Flashcards in Lecture 21 - Motor Neuron Disease Deck (29):
1

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

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

2

Most common form of motor neuron disease

Amyotrophic lateral sclerosis

3

Upper motor neurons

Originate in the brain, brainstem
Don't directly innervate muscle

4

Lower motor neurons

Originate in the spinal cord
Directly innervate muscles

5

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

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

6

Most common cause of death in MND

Respiratory failure

7

Peak age of onset of MND

45-60

8

Effect on muscles of MND

Muscle atrophy

9

MND effect on sensory nerves

Sensory nerves are spared

10

Diagnosis of MND
1)
2)
3)

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

11

Prognosis of MND
1)
2)

1) Confined to wheelchair within 1-2 years
2) Death within 3-5 years

12

Only approved MND therapy

Riluzole ('Rilutek')
Moderate clinical efficacy

13

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

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

14

Possible environmental factors in MND
1)
2)
3)

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

15

Number of cases of MND with a sporadic basis

Over 90%

16

Effect of riluzole

Increases GLT1 uptake of glutamate into astrocyte

17

Mutant gene associated with familial MND

Copper/zinc superoxide dismutase (SOD1)

18

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

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

19

Reaction involving SOD1

SOD1 + O2-* + 2H+ --> SOD1 + H2O2

20

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

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

21

Inheritance pattern of most familial MND

Autosomal dominant

22

Old theory of development of familial MND

More mutant SOD1 leads to more severe phenotype

23

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

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

24

New theory of development of familial MND

More metal-deficient SOD1 leads to more severe phenotype

25

Possible states of SOD1
1)
2)
3)

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

26

Effect of drug being trialled

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

27

Toxic form of SOD1

Metal-deficient

28

Why is Apo SOD1 not toxic?

It is broken down extremely rapidly.

29

Possible diagnostic tool for MND
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2)
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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