Protein misfolding in neurodegenerative diseases

Question 1

What are the 2 types of secondary structures for protein?

Answer 1

1. α-Helix

2. ß-sheet (parallell or anti-parallell)

Question 2

What are the different forces that stabilizes protein structures?

Answer 2

• Secondary structures (α-Helix or ß-sheet)
• Hydrophobic interactions
• Disulfide bonds
• Hydrogen bonds
• Electrostatic attractions

Question 3

What is the native state of a protein?

Answer 3

Completely folded protein because it requires less energy 
Amyloid fibrils (protein misfolding) demand even less energy

Question 4

What are the 3 factors influencing protein folding and aggregation?

Answer 4

1. Molecular chaperones and the ubiquitin-proteasome pathway (Ub) prevent aggregation by facilitating refolding or degradation, respectively
2. An increased population of misfolded proteins as a result of genetic or other factors may lead to saturation of these defense mechanisms => increased protein aggregation and amyloid formation
3. Partially folded proteins associate with each other to form small, soluble oligomers that may undergo further assembly into protofibrils, oligomeric pores or mature fibrils (amyloid)

Question 5

What is Alzheimer’s disease, what is its pathologies and what are the risk factors?

Answer 5

• Progressive neurodegeneration, most common form of dementia, causes memory impairment and there is no cure
• Plaque formation, loss of synapses, loss of neurons resulting in shrinkage of the brain and inflammation
• High age (most important risk factor), ApoE4, family history, mutations, life style and environment

Question 6

What are amyloid composed of?

Answer 6

Protein fibrils (resistant to proteolysis)

Question 7

Why is Aß important in Alzheimer’s disease (AD)?

Answer 7

• Aβ plaques are always present in AD brain
• Aβ levels in brain correlate with degree of dementia
• Aβ becomes neurotoxic upon polymerization
• All familial AD mutations => increased Aβ
• Protective mutation in APP => reduced Aβ production
• Extra copy of APP (Down’s syndrome) => early onset AD

Question 8

What can be said about the protein causing Parkinson’s disease?

Answer 8

• Lewy bodies are found in affected cells
• Fibrils formed by α-synuclein is the main component
• Oligomers seem to be neurotoxic
• Oligomers can spread from neuron to neuron
• Oligomers could be pharmaceutical targets

Question 9

Why and how is tau a target for treatment?

Answer 9

Tau fibrils are present in many neurodegenerative diseases. Thus, inhibition of tau polymerization could be a therapeutic target for many neurodegenerative diseases
Tau as a target:
- inhibition of tau hyper-phosphorylation
- inhibition of tau aggregation with small molecules
- active immunization (inject the protein like vaccine)
- passive immunization (inject antibodies => currently used because safer method)

Question 10

What is transthyretin (TTR) amyloidogenesis cascade?

Answer 10

For amyloidogenesis to occur, the TTR tetramer must:
• Dissociate into four folded monomers
• Undergo partial denaturation in order to…
• Misassemble into a spectrum of aggregate structures including cross-β-sheet amyloid fibrils
=> treatment is also aiming for this cascade

Question 11

What is prion disease and what causes it?

Answer 11

• Fatal progressive neurodegeneration accompanied by cognitive and motor dysfunctions (no cure)
• Caused by the prion protein (PrP) found in amyloid plaques