Autophagy

Question 1

1. Differentiate between two main types of autophagy: macroautophagy and chaperone-mediated autophagy.
2. Describe the process of macroautophagy.
3. Describe the rationale behind autophagy’s protective action against neurodegeneration.
4. Identify mechanisms by which apoptosis induction and autophagy are connected.

Answer 1

x

Question 2

Understand differences between two main types of autophagy- macroautophagy and chaperone-mediated autophagy.

Answer 2

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 3

Describe process of macroautophagy.

Answer 3

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 4

Describe rationale behind autophagy’s protective action against neurodegeneration.

Answer 4

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 5

Identify mechanisms by which apoptosis induction and autophagy are connected.

Answer 5

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.