Cellular mechanisms in neurodegeneration

Question 1

What characterizes most of neurodegenerative diseases?

Answer 1

Deposition of abnormal proteins => aggregation

Question 2

What are the 2 types of selectively vulnerable cell types and what causes them?

Answer 2

Primary vulnerable cells: those affected in the initial stage of the disease
Secondary vulnerable cells: those affected later, in regions where the pathology has spread to

• Protein conformation (tau protein mutations causes different conformations)
• Genomics (risk loci genetically involved in disease pathogenesis)
• Protein supersaturation (cell populations expressing different levels of proteins)
• Protein homeostasis (clearance mechanisms)
• Differential expression of calcium-buffering proteins

Question 3

What is the prion principle of pathological transmission in protein aggregation?

Answer 3

Protein aggregation has the capability of self-propagation

=> linked to the disease progression

Question 4

What are the 2 ways pathogenic proteins aggregates meditate cell-to-cell transmission and what are the 5 ways it enters the cell?

Answer 4

1. A small amount of protein aggregates can be released into the extracellular space in the ‘naked’ form
2. Via membrane-bound vesicles such as exosomes
3. Directly penetrate the plasma membrane of the recipient (neuron)
4. Enter by fluid-phase endocytosis
5. Enter by receptor-mediated endocytosis
6. Exosomes containing pathogenic proteins may fuse with the membrane of the recipient neuron
7. Nanotubes that directly connect the cytoplasm of two cells (new)

Question 5

What are the evidence that transneuronal propagation of pathogenic proteins and metabolites can happen from gut to the brain?

Answer 5

Clinical evidence: patients who have undergone truncal vagotomies for the treatment of peptic ulcer disease appear to have a decreased risk of developing Parkinson’s disease

Pre-clinical evidence: inoculating the duodenum of aged mice with α-Syn preformed fibrils promotes progression of p-α-Syn to the brain

Question 6

How does protein aggregation caused neurodegeneration disrupt neurons (6 things)?

Answer 6

• Synaptic toxicity
• Protein quality control
• Autophagy–lysosome pathway
• Mitochondria homeostasis
• Network dysfunction
• Neuroinflammation

Question 7

Which part of the neuron is the most vulnerable to neurodegeneration?

Answer 7

The axon => loss of synaptic density and function

Question 8

What can be said about mitochondria in neurodegeneration?

Answer 8

In all neurodegeneration there is a loss of mitochondria which leads to decrease of neural activity and function

Question 9

How is mitochondria functions altered in neurodegeneration (5 things)?

Answer 9

1. Dysfunctionning regulation of Ca2+ signaling
2. Decrease provision of ATP
3. Increase production of ROS
4. Increase meditation of apoptosis
5. Altered synthesis of phospholipids and cholesterol

Question 10

What are MERCS, why are they important and what happens during neurodegeneration?

Answer 10

MERCS = Mitochondria-ER Contact Sites
- Calcium transfer
- Lipid and cholesterol synthesis 
- Mitochondria fission 
- Autophagosome formation 
=> all these functions are affected in neurodegeneration

Question 11

What can be said about glucose and early stages of neurodegenerative disorders?

Answer 11

In all early stages of neurodegenerative disorders there is a decrease of glucose utilization (hypometabolism)