Autophagy Flashcards
What are the functions of autophagy/lysosomal pathways?
Recycling of nutrients
Downregulation of signalling pathways
Cellular remodelling
Killing of intracellular pathogens
Homeostasis
Removing damaged components
What is the UPS?
Ubiquitin-Proteasome system: Proteins are tagged with ubiquitin and recognised by the UPS. Major turnover pathway for short-lived proteins, doesn’t require a lysosome. Some bacteria have a similar system called pupylation.
What is macroautophagy?
Lysosomal, bulk digestion pathway using autophagosomes. Can digest entire organelles, the molecules released support metabolism.
What is microautophagy?
Lysosomal, engulfment of cytoplasmic material, lower volume than macroautophagy.
What is CMA?
Chaperone-mediated autophagy. Proteins with a CMA-targeting motif are recognised by chaperones which deliver them to the lysosome for degradation. Similar to Microautophagy but much more specific.
Tell me about nutrient recycling
Autophagy is rapidly upregulated under starvation conditions, causes non-selective bulk-degradation of the cytosol.
Autophagy deficient mice die during neonatal starvation, likewise, autophagy-deficient cells die during starvation conditions. Cancer cells in solid tumours require autophagy until the vascular system develops.
Tell me about cellular remodelling
Autophagy is the only mechanism that can degrade entire organelles. In erythropoiesis, the nucleus, mitochondria and ER are removed. Sperm-derived mitochondria are removed after eggs are fertilised.
Tell me about the removal of damaged components
Overtime, cellular components accumulate damage, can be due to oxidative stress and misfolding. Particularly relevant to ageing and neurodegenerative diseases; as you age your autophagic flux capacity decreases. Long-lived cells and muscle cells are more susceptible.
Tell me about the role of autophagy in killing intracellular pathogens/viruses
Many pathogens have evolved to escape or survive in lysosomes & escape into the cytoplasm. This includes Mycobacterium and some Salmonella strains.
What can we use autophagy for?
Inhibit it to starve cancer cells or reduce the cellular uptake of pathogens.
Upregulate it to reduce ageing, reduce muscle dystrophy, reduce neurodegeneration, prevent cancers developing, kill more pathogens/viruses.
How many proteins are involved in autophagy, and what initiates it?
There are 50-60 proteins involved (atg genes). VLK1 complex initiates the pathway (it’s a kinase), and it’s controlled by mTORC1 & AMPK. Initiation leads to autophagosome formation & elongation until it closes and fuses with a lysosome.
What is the role of autophagy in neurodegenerative diseases?
Autophagy is a house keeping function ensuring that misfolded or damaged proteins are degraded.
Neurons are particularly sensitive to misfolded proteins due to their long lifespan and transport of proteins over long distances.
Dysfunctional autophagy can lead to accumulation of ubiquitinated aggregates & increased apoptosis. Neurons cannot reproduce.
What causes Huntington’s disease?
Polyglutamine expansion in the huntingtin protein. When Q<18, individual is healthy, when Q>35, huntingtin protein is disease causing. PolyQ huntingtin protein is misfolded and aggregates where it is ubiquitinated, usually it would be removed by proteasomal degradation but it can form aggresomes which have to be removed via autophagy.
Why is polyQ huntingtin protein toxic?
Can lead to loss of normal huntingtin protein function.
Interacting proteins are sequestered & degraded
Can form toxic oligomers and aggresomes.
Can damage the proteasome/proteasomal system
Sequester adaptors required for other damaged proteins
Tell me about the molecular basis of Parkinson’s disease
Affects 1-2/1000 people in the UK. Involves the loss of inhibitory dopaminergic neurons. α-synuclein is rarely mutated itself.
α-synuclein is usually degraded via CMA, the A53T mutation blocks the CMA.