Lecture 21 - Autophagy 2 Flashcards
What is macro (autophagy)?
a mechanism to digest intracellular material
What are the 4 functions of autophagy?
- Recycling nutrients
- Damaged protein/organelle removal
- Cellular remodelling
- Intracellular pathogen removal
What is Atg8?
an autophagy-related (Atg) protein. It plays a key role in forming the autophagosome, a structure that captures and transports damaged or unnecessary cell components to be degraded.
Atg8 is embedded in membrane of phagosome
What occurs to damaged mitochondria?
It is selectively removed
What does CCCP do?
CCCP induces mitochondrial stress and can cause mitochondrial dysfunction.
What occurs in cells that lack autophagy?
Accumulate protein aggregates
What does neuronal-specific autophagy disruption in mice cause?
1 - accumulation of ubiquitinated aggregates
2 - increased apoptosis
What are proteinopathies in neurodegeneration?
- Huntingtin aggregates in Huntington’s
- Amyloid B plaques in Alzheimer’s
- A-synuclein in Parkinsons
What causes Huntington’s disease?
Caused by polyglutamine (polyQ) expansion in Huntingtin protein
How many polyglutamine (polyQ) is considered healthy?
Less than 18
How many polyglutamine (polyQ) is considered disease-causing?
More than 35
What mechanisms can lead to toxicity?
- Misfolding & aggregation (loss of normal function)
- Ubiquitination (toxic oligomer)
- Aggresome formation (successful)
- Autophagic degradation (adaptor sequestration)
- successful proteosomal degradation (successful)
Describe Parkinson’s & mitochondrial disfunction
- Damaged mitochondria also accumulate in Parkinson’s
- Mitochondria are he main source of Reactive Oxygen Species (ROS)
- ROS damages cellular components (lipids, proteins & DNA)
Describe a-synuclein mutations (rare)
- a syn normally degraded by chaperone-mediated autophagy
- mutated versions block the CMA pathway, causing toxicity
- comes from A53T mutation
Describe autophagy & Parkinson’s disease
- affects 1-2 per 1000 of the UK population
- loss of dopaminergic neruons
- main neuropathology is aggregates of a-synucleic (Lewy Bodies)
Complex genetics, with only 5-10% of cases familial, with a-synuclein itself rarely mutated
What is the hypothesis as what might cause Parkinson’s?
Parkinson’s may be caused by mitochondrial-derived oxidative damage
What is mitophagy?
Mitophagy is a process in which damaged or dysfunctional mitochondria (the energy-producing structures in cells) are recognized and removed by the cell.
How does PINK1 regulate mitophagy?
- mitochondrial kinase
- loss of function in 5-10% sporadic
- early-onset Parkinson’s
What regulates mitophagy?
PINK1 & PARKIN
How does PARKIN regulate mitophagy?
- Cytosolic E3 ubiquitin ligase mutated in 50% of autosomal recessive 10-15% of sporadic early-onset Parkinson’s
How does damaged mitochondria lead to neurodegeneration?
Damaged mitochondria leads to release of ROS (reactive oxygen species), which further damages other components, as well as other mitochondria, which then leads to more ROS being released. This will lead to a feedback cycle.
How is autophagy a general cause of neurodegeneration?
- impaired autophagosome formation
- disrupted lysosomal function
- secretion
- inhibited autolysosome formation
- autophagic cargo
- disruption of cargo recognition
What causes cancer?
Cancer is caused by accumulation of DNA damage
What is autophagy?
A tumour suppressive
What is pro-oncogenic autophagy?
autophagy is unrelated in hypoxia (lack of oxygen), nutrient-poor regions
- blocking autophagy causes necrosis or apoptosis
What effect does autophagy have on apoptosis?
- Autophagy also inhibits apoptosis
- this drives tumour survival & chemotherapy resistance
How is autophagy anti-oncogenic?
- cell homeostasis
- damage removal
- reduced ROS/genotoxicity
- reducing inflammation
How is autophagy pro-oncogenic?
- survival during oxygen or nutrient shortage
- prevention of apoptosis
- survival during chemotherapy
What are strategies for autophagy therapeutics?
- blocking survival to metabolic stress with autophagy inhibitors
- inhibit autophagy to increase apoptosis during chemotherapy
- elevate autophagy to remove damage and prevent cancer
