Autophagy

Question 1

Autophagy

Answer 1

mechanism to digest intracellular material

Question 2

Why do cells need degradation?

Answer 2

homeostasis
removing damaged components
signalling
recycling nutrients
reprogramming cells for differentiation

Question 3

What are the different mechanisms of degradation?

Answer 3

ubiquitin/proteosome system
macroautophagy
chaperone-mediated autophagy
microautophagy

Question 4

Proteosome

Answer 4

non-lysosomal
degrades individual proteins
major turnover route for short lived proteins

Question 5

Macroautophagy

Answer 5

lysosomal
bulk digestion pathway
can remove whole organelles
molecules released can support metabolism

Question 6

Chaperone mediated autophagy

Answer 6

lysosomal
only degrades individual proteins
turns over specific generally long lived proteins and relatively low capacity

Question 7

Nutrient recycling

Answer 7

autophagy is rapidly upregulated under starvation which causes non-selective bulk degradation of the cytosol
wihout autophagy cells die under starvation
cancer cells in solid tumours need it to survive

Question 8

Cellular remodelling

Answer 8

autophagy is the only mechanism to degrade organelles and is essential to from specific cell types

Question 9

Removal of damaged components

Answer 9

cellular componnents accumulate damage over time
cell are continuously damaged and reduced autophagy is part of age related degeneration

Question 10

What cells are most susceptible to age related reductions in autophagy?

Answer 10

long lived metabolic cells
neurons and muscle

Question 11

What processes require organelle autophagy to form specific cell types?

Answer 11

erythropoiesis
removal of sperm derived mitochondria

Question 12

Dietary restriction hypothesis

Answer 12

starvation/exercise → increase in autophagy → increase in damage repair

Question 13

Damaged protein/organelle removal in disease

Answer 13

ageing, muscular dystrophy, neurodegeneration, cancer

Question 14

Intracellular pathogen removal examples

Answer 14

tuberculosis, MRSA and viruses

Question 15

What happens when neuronal cells lack autophagy?

Answer 15

accumulation of ubiquitinated aggregates
increased apoptosis and necrosis

Question 16

Huntingtons disease

Answer 16

caused by polyglutamine (polyQ) expansion in the huntingtin protein:
midfolding and aggregation → ubiquitination → aggresome formation/ proteosomal degradation → autophagic degradation

Question 17

Parkinsons disease

Answer 17

main neuropathology is aggregates of a-synuclein or lewy bodies
complex genetics but a-synuclein is rarely mutated

Question 18

a-synuclein

Answer 18

normally degraded by chaperone mediated autophagy
mutated versions block this causing toxicity in parkinsons

Question 19

What else accumulates in parkinsons disease?

Answer 19

damaged mitochondria
may be caused by mitochondrial derived oxidative damage as they are the main source of ROS

Question 20

PINK1

Answer 20

mitochondrial kinase which shows loss of function mutation in some sporadic early onset parkinsons

Question 21

PARKIN

Answer 21

cytosolic E3 ubiquitin ligase
mutated in half of autosomal recessive parkinsons and a some of sporadic early onset

Question 22

How is autophagy tumour recessive?

Answer 22

decrease in damaged organelles
protein toxicity and ROS stops oxidative stress and DNA damage, and therefore tumorigenesis

Question 23

Beclin 1

Answer 23

monoallelically deleted in 40-75% of ovarian, breast and prostate carcinomas

Question 24

Where is autophagy unregulated?

Answer 24

in hypoxic, nutrient poor tumour regions

Question 25

How is lack of autophagy related to cancer?

Answer 25

cancer can be caused by accumulation of DNA damage

Question 26

How is autophagy anti-oncogenic?

Answer 26

cell homeostasis
damage removal
reduced ROS and genotoxicity
reduced inflammation

Question 27

How can autophagy be pro-oncogenic?

Answer 27

survival during oxygen or nutrient storage
prevention of apoptosis
survival during chemotherapy

Question 28

Autophagy based therapies

Answer 28

blocking survival to metabolic stress with autophagy inhibitors
inhibiting autophagy to increase apoptosis during chemo
elevating autophagy to remove damage and prevent cancer