Cellular stress responses

Question 1

Give example of factors which can induce cellular stress

Answer 1

UV light 
toxic compounds 
starvation 
high temperature 
change in pH 
hypoxia

Question 2

Give example of factors that can induce cellular stress in AD or PD?

Answer 2

• toxic protein aggregates of A-beta, alpha synuclein and tau
• damaged, dying and dead cells
• inflammation
• normal cellular functions cannot be maintained
• downstream effects of these

Question 3

Name 4 different autophagy pathways and how they work?

Answer 3

• Macroautophagy: main mechanism that maintaines cellular homeostasis. Intracellular cargo is recognized through interactions with specific adaptor proteins e.g. p62 (p62 interacts with both modified substrates and the LC3 autophagosomal receptor)
• Microautophagy: mediated by direct, non-selected lysosomal engulfment of the cytoplasmic cargo
• Chaperone-mediated autophagy (CMA): cytosolic proteins carrying a specific motif are recognized by a group of chaperones and targeted to the lysosome, where they interact with LAMP-2A
• Endocytosis: endosomes carrying extracellular components fuse with the lysosome. Occationally this occurs first by fusion with autophagosomes

Question 4

What is the main regulator of autophagy? And how does it effect autophagy?

Answer 4

mTOR (target of rapamycin) is the master regulator of autophagy. It inhibits the autophagy. Starvation or other cellular stress (intracellular Ca, hypoxia etc.) can inactivate mTOR

Question 5

How does mitophagy occur and why?

Answer 5

Mitophagy occurs with damaged mitochondria/mitochondria fragments. the LC3 protein helps form the double membrane of the autophagosome which engulfs the mitochondria and then fuses with the lysosome and the mitochondria is degradated

Question 6

What is mitochondrial fusion and fission?

Answer 6

Mitochondrial fusion: a fragment of mitochondria (made by biogenesis) fuse with excisting mitochondria other mitochondria fragments.
Mitochondrial fission: division of excisting mitochondria into smaller mitocondrial or into mitochondrial fragments.

Question 7

What is compromised mitophagy?

Answer 7

It removes dysfunctional mitochondria through a macroautophagy pathway

Question 8

How does compromised mitophagy affect neurons in AD?

Answer 8

Compromised mitophagy causes decreased energy production and increased oxidative stress. This leads to increased accumulation of amyloid beta and hyperphosphorylated tau, degradation defects and ineffective transportation

Question 9

Briefly explain the relationship between mitochondrial damage and oxidative stress?

Answer 9

Mitochondrial damage is both the main contributor to oxidative stress and one of the major consequences of oxidative stress

Question 10

What are stress granules?

Answer 10

membrane-less dense aggregations in the cytosol composed of RNA and proteins

Question 11

What are the mechanisms of the spreading of toxic amyloid-beta/alpha synuclein/tau aggregates

Answer 11

• Extracellular vesicles
• tunneling nanotubes
• direct membrane contact
• secretion of “free” protein aggregates

Question 12

Name 2 types of extracellular vesicle mediated uptake of toxic e.g. A-beta?

Answer 12

• by macropinocytes

- by receptor-mediated phagocytosis

Question 13

What happens after the vesicles reached the cytosol in extracellular vesicle mediated uptake of e.g. A-beta?

Answer 13

the material is transported to the early endosomes where it can be either recycled back to the plasma membrane or be degradated

Question 14

What are tunneling nanotubes? And how /when are they created/ what is their function?

Answer 14

they are extensions of a cell cytoskelton that reaches the neighboring cells. It is done by actin polymerization . It is a communication and transfer mechanism. It is increased in stressful situations