Lecture 21 - Motor Neuron Disease Flashcards
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
Most common form of motor neuron disease
Amyotrophic lateral sclerosis
Upper motor neurons
Originate in the brain, brainstem
Don’t directly innervate muscle
Lower motor neurons
Originate in the spinal cord
Directly innervate muscles
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
Most common cause of death in MND
Respiratory failure
Peak age of onset of MND
45-60
Effect on muscles of MND
Muscle atrophy
MND effect on sensory nerves
Sensory nerves are spared
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
Prognosis of MND
1)
2)
1) Confined to wheelchair within 1-2 years
2) Death within 3-5 years
Only approved MND therapy
Riluzole (‘Rilutek’)
Moderate clinical efficacy
Genetic factors in MND 1) 2) 3) 4) 5)
1) Copper/Zinc superoxide dismutase
2) TDP43
3) Optineurin
4) Angiogenin
5) C9ORF72
Possible environmental factors in MND
1)
2)
3)
1) Head trauma
2) Military service
3) Chemical toxins
Number of cases of MND with a sporadic basis
Over 90%
Effect of riluzole
Increases GLT1 uptake of glutamate into astrocyte
Mutant gene associated with familial MND
Copper/zinc superoxide dismutase (SOD1)
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
Reaction involving SOD1
SOD1 + O2-* + 2H+ –> SOD1 + H2O2
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
Inheritance pattern of most familial MND
Autosomal dominant
Old theory of development of familial MND
More mutant SOD1 leads to more severe phenotype
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
New theory of development of familial MND
More metal-deficient SOD1 leads to more severe phenotype
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)
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
Toxic form of SOD1
Metal-deficient
Why is Apo SOD1 not toxic?
It is broken down extremely rapidly.
Possible diagnostic tool for MND 1) 2) 3) 4) 5)
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
