Amyotrophic lateral sclerosis and Alzheimer's

Question 1

Describe the differences between upper motor neuron lesions and lower motor neuron lesions.

Answer 1

Upper: Lesions above the anterior horn. Spastic muscle tone, hyper-reflexia, babinski sign (+)

Lower: Flaccid muscle tone and babinski sign (-)

Babinski sign - when big toe bends upward while other toes spread out.

Question 2

What is the most commonly mutated gene in ALS, and what does it do?

Answer 2

C9orf72 - function is unknown, but there’s a region in the intron with GGGGCC repeat.

SOD is involved in misfolding and ER stress.

Question 3

What is Amyotrophic lateral sclerosis (ALS)?

Answer 3

Progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord.

Limb weakness, bulbar impairment (speech and swallowing), respiratory muscle involvement (cause of mortality)

Question 4

T/F: Muscular atrophy is associated with upper motor neuron lesions in early stages.

Answer 4

False, atrophy is associated with lower motor neurons.

Normally don’t get muscles smaller at earlier stages.

Question 5

T/F: Decreased deep tendon reflexes are signs of upper motor neuron lesions.

Answer 5

False, we’d expect increase. Lower motor neuron is more active and upper motor neuron is not correcting for it.

Question 6

T/F: Loss of C9orf72 protein in the nucleolus of motor neurons is the pathogenic mechanism in ALS.

Answer 6

False

Question 7

T/F: Mislocalization of TDP-43 in the cytoplasm causes mRNA splicing defect in ALS.

Answer 7

True

Question 8

Describe how the formation of cytoplasmic TDP-43 body is associated with ALS?

Answer 8

TDP-43 is an RNA binding protein that is involved in splicing inside the nucleus.

Mislocalized to the cytoplasm and forms RNA granules in ALS - leads to defective mRNA splicing.

Question 9

List 2 possible mechanisms how hexanucleotide repeat causes ALS.

Answer 9

(GGGGCC)n repeats in C9orf72. 20 is normal, up to 1000 in ALS.

1) Loss of function of C9orf72 leads to abormal microglial responses.
2) Gain of function of RNA foci leads to sequestration of RNA-binding proteins.

Question 10

What are the 2 pathological signatures of Alzheimer’s disease?

Answer 10

1) Amyloid plaques are clumps of beta-amyloids, which destroy connections between nerve cells
2) Neurofibrillary tangles are aggregates of hyperphosphorylated tau protein

Question 11

What is Aβ hypothesis, and how was it tested in clinical trials?

Answer 11

Amyloid plaques:

• Extracellular protein aggregates
• Produced from amyloid precursor protein (APP)
• If APP gets misprocessed, you’ll have amyloid β protein to form aggregates

Tested via EPOCH trial. Use BACE1 inhibitor, but Phase III clinical trial failed.