ALS - Clinical Features and Genetics

Question 1

What is ALS?

Answer 1

A rapidly progressive neurodegenerative disease and the most common type of MND

Question 2

What pathological process characterises ALS?

Answer 2

Degeneration of motor neurons

Question 3

What is the average age of onset of ALS?

Answer 3

55

40-70

Question 4

What is the cause of ALS?

Answer 4

Umknown

Question 5

How many deaths does ALS cause per year?

Answer 5

2 per 100,000

Question 6

What are the 3 types of ALS?

Answer 6

Sporadic
Familial
Guamian

Question 7

What are the main clinical symptoms observed in the limbs?

Answer 7

Weakness
Decreased dexterity
Foot drop
Leg stiffness
Tripping
Poor balance

Question 8

What are the main clinical symptoms of ALS observed in the throat?

Answer 8

Difficulty chewing/swallowing

Slurred speech

Question 9

How does ALS progress?

Answer 9

Slowly become unable to write, walk or roll over in bed

Become breathless on exertion or lying flat

Difficulty breathing and paralysis inevitable

Question 10

What is the most common familial mutation in SOD1?

Answer 10

A4V

Alanine to valine

Question 11

What is the mean survival with the A4V mutation of ALS?

Answer 11

1 year from diagnosis

Question 12

What is the known sporadic mutation?

Answer 12

C9orf72

Question 13

What are the known familial mutations?

Answer 13

C9orf72 (24%)
SOD-1 (20%)
TDP-43 (5%)
FUS (5%)

Question 14

What is the normal function of TDP-43?

Answer 14

Process gene transcription in the mitochondria

Question 15

What does TDP-43 do in ALS?

Answer 15

Aggregates in the cytoplasm

Question 16

What is TDP-43 mutation in ALS associated with?

Answer 16

Reduction in axonal length and cellular toxicity

Question 17

How do transgenic mice confirm TDP-43 involvement in ALS?

Answer 17

Mutated TDP-43 mice have an MND phenotype with no control over voluntary movement

(due to lack of extended physiological proprioceptive system)

Question 18

What is SOD-1

Answer 18

The gene encodes for SOD-1 metalloprotein which chelates superoxides Cu/Zn

SOD-1 = superoxide dismutase 1

Question 19

What is the normal function of SOD-1?

Answer 19

Converts super-oxide radicals to hydrogen peroxide and oxygen

((SOD = superoxide dismutase)

Question 20

Where is SOD-1 normally found?

Answer 20

Cytosol
Nucleus
Mitochondrial membrane

Question 21

Why is it thought that SOD-1 mutations are gain of function?

Answer 21

SOD-1 KO mice don’t show any huge effects and defo no MND phenotype

Question 22

How does mutant SOD-1 affect proteasomes?

Answer 22

Mutated SOD-1 is more likely to aggregate
These lose function and need to be degraded
There is a lot of it which clogs up the proteasomes so it cannot function properly

Question 23

How does mutant SOD1 affect the mitochondria?

Answer 23

Directly causes dysfunction. Disrupts cytochrome C associated with the inner mitochondrial membrane
This interferes with respiration.
There is then production of ROS which cant be cleared leading to damage and degeneration

Question 24

How does mSOD1 mediate oxidative damage?

Answer 24

Structural change in SOD1 leaves its Cu site open to abberant substrates
Causes breakdown of H2O2 to hydroxyl radicals

Question 25

Which compound other than H2O2 can become a substrate for mSOD1?

Answer 25

Peroxynitrite

Question 26

What does peroxynitrite bonding to mSOD1 cause?

Answer 26

Nitration of tyrosine residues in target proteins to kill cells

Question 27

How does mSOD1 affect mitochondrial function?

Answer 27

Causes mitochondrial swelling in human and mice
Aggregates in mitochondira, leads to ETC dysfunction
Disrupts cytochrome C
Produces ROS