Autophagy

Question 1

1. Differentiate between two main types of autophagy: macroautophagy and chaperone-mediated autophagy.

Answer 1

Macroautophagy:

• (best studied)- form a double membrane vesicle that captures cytosolic components/organelles.
• Then fuse with lysosome where hydrolases degrade contents of autophagosome.

Chaperone-mediated:
-recognition of specific proteins that contain a specific recognition sequence (based on amino acid sequence KFERQ). Direct binding and delivery to lysosome.

Question 2

2. Describe the process of macroautophagy.

Answer 2

• Activate a PI3K complex that allows nucleation of a membrane that will eventually form autophagosome.
• Regulation of protein conjugation events to extend membrane.
• Randomly capture, or specifically deliver cargo to the extending autophagosome, then join the membranes to close the vesicle.
• Fuse with lysosome.
• Recycle amino acids and other macromolecular precursors.

Question 3

3. Describe the rationale behind autophagy’s protective action against neurodegeneration.

Answer 3

• Aggregate-prone proteins (e.g. those with expanded stretches of glutamine residues in diseases like Huntington’s disease) will cause neuronal cell death.
• Autophagy degrades the aggregate-prone proteins (perhaps after they have started to form small aggregates).
• No toxic stimulus, no neuronal cell death.

Question 4

4. Identify mechanisms by which apoptosis induction and autophagy are connected.

Answer 4

• Many proteins - e.g. Bcl-2 - that regulate apoptosis/ cell death, also control autophagy–remember, this could create problems in interpreting results of therapeutic interventions designed to target these proteins.
• Apoptotic proteases (caspases) can cleave essential autophagy regulators inactivating them and therefore blocking the process of autophagy.
• In some cases, -e.g. with starvation-induced cell death, it is easy to see why autophagy would protect– it provides essential nutrients at least in the short term.
• In others, e.g. stress-induced cell death from chemotherapy etc. its less clear why autophagy would be protective.