ALS - Clinical Features and Genetics Flashcards
What is ALS?
A rapidly progressive neurodegenerative disease and the most common type of MND
What pathological process characterises ALS?
Degeneration of motor neurons
What is the average age of onset of ALS?
55
40-70
What is the cause of ALS?
Umknown
How many deaths does ALS cause per year?
2 per 100,000
What are the 3 types of ALS?
Sporadic
Familial
Guamian
What are the main clinical symptoms observed in the limbs?
Weakness Decreased dexterity Foot drop Leg stiffness Tripping Poor balance
What are the main clinical symptoms of ALS observed in the throat?
Difficulty chewing/swallowing
Slurred speech
How does ALS progress?
Slowly become unable to write, walk or roll over in bed
Become breathless on exertion or lying flat
Difficulty breathing and paralysis inevitable
What is the most common familial mutation in SOD1?
A4V
Alanine to valine
What is the mean survival with the A4V mutation of ALS?
1 year from diagnosis
What is the known sporadic mutation?
C9orf72
What are the known familial mutations?
C9orf72 (24%)
SOD-1 (20%)
TDP-43 (5%)
FUS (5%)
What is the normal function of TDP-43?
Process gene transcription in the mitochondria
What does TDP-43 do in ALS?
Aggregates in the cytoplasm
What is TDP-43 mutation in ALS associated with?
Reduction in axonal length and cellular toxicity
How do transgenic mice confirm TDP-43 involvement in ALS?
Mutated TDP-43 mice have an MND phenotype with no control over voluntary movement
(due to lack of extended physiological proprioceptive system)
What is SOD-1
The gene encodes for SOD-1 metalloprotein which chelates superoxides Cu/Zn
SOD-1 = superoxide dismutase 1
What is the normal function of SOD-1?
Converts super-oxide radicals to hydrogen peroxide and oxygen
((SOD = superoxide dismutase)
Where is SOD-1 normally found?
Cytosol
Nucleus
Mitochondrial membrane
Why is it thought that SOD-1 mutations are gain of function?
SOD-1 KO mice don’t show any huge effects and defo no MND phenotype
How does mutant SOD-1 affect proteasomes?
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
How does mutant SOD1 affect the mitochondria?
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
How does mSOD1 mediate oxidative damage?
Structural change in SOD1 leaves its Cu site open to abberant substrates
Causes breakdown of H2O2 to hydroxyl radicals
Which compound other than H2O2 can become a substrate for mSOD1?
Peroxynitrite
What does peroxynitrite bonding to mSOD1 cause?
Nitration of tyrosine residues in target proteins to kill cells
How does mSOD1 affect mitochondrial function?
Causes mitochondrial swelling in human and mice
Aggregates in mitochondira, leads to ETC dysfunction
Disrupts cytochrome C
Produces ROS
