Lecture 22- Autophagy II Flashcards
Describe the role of autophagy as a housekeeping process
Actively works at a low basal rate inside the cell to remove any damaged material in the cell.
Does this by selectively removing damaged proteins and organelles
What accumulates in cells lacking autophagy?
Protein aggregates
Why are neurons particularly sensitive to damage?
Because they are extremely long-lived cells, metabolically active and have long protrusions. This makes trafficking the proteins more difficult/less efficient
What does neuronal-specific autophagy disruption is mice cause?
- Accumulation of ubiquitinated aggregates
2. Increase apoptosis
How can apoptosis be viewed/studied?
Using TUNEL staining
What are proteinopathies?
Diseases where proteins are abnormally self-associating and aggregating due to confirmations changes
What proteinopathy causes Huntington’s disease?
Huntingin protein aggregates
What proteinopathy causes Alzheimer’s disease?
Amyloid-beta plaques aggregates
What proteinopathy causes Parkinson’s disease?
alpha-synclein aggregates
What is similar and different in the protein aggregates in Huntington’s, Alzheimer’s and Parkinson’s disease?
All share common phenotype that they have accumulation of ubiquitinated inclusions
However the proteins and areas in the brain where accumulation occurs is different so the symptoms can vary
What causes Huntington’s disease?
Caused by polyQ expansion because it causes a mutation on the Huntingtin protein, making it missfold and aggregate
These proteins accumulate over time, causing the disease to worsen as you age
Why does Huntington’s disease worsen with age?
Your lysosomal capacity and therefore your ability to remove the protein aggregates deceases with age.
As you get older, the accumulation of protein aggregates outpaces the ability to degrade the protein causing you to accumulate them
What is the association of polyQ expansion and Huntington’s disease?
The more polyQ you have, the more susceptible to the disease you are and the earlier the onset
PolyQ less than 18 = healthy
PolyQ more than 35 = disease causing
What are some mechanisms of toxicity?
- Loss of normal protein function
- Toxic oligomer
- Aggresomes themselves may be toxic
- Proteasomal damage
- Adaptor sequestration
What does the aggregation of alpha-synuclein cause in Parkinson’s disease?
Causes a loss of dopinergic neurons
How is alpha-synuclein protein normally degraded?
- By chaperone-mediated autophagy
- The LAMP2 receptor on the lysosome surface is able to recognise specific amino acid sequences/proteins
- These are then transported directly into the lysosome to be degraded
How does alpha-synuclein mutations affect chaperone mediated autophagy?
- The A53T mutated alpha-synuclein blocks the CMA pathway
- The protein can still bind to the LAMP2 receptor but cannot be transported into the lysosome
- Therefore, mutated alpha-synuclein cannot be degraded, forms aggregates and causes toxicity
How does damaged mitochondria link with Parkinson’s disease?
- Damaged mitochondria accumulate in Parkinson’s and are a big source of ROS
- ROS damages cellular components
- Therefore, Parkinson’s maybe caused by mitochondrial-derived oxidative damage
What genes have been identified in familial Parkinson’s?
PINK1 and PARKIN genes
How do PINK and PARKIN proteins normally function?
- PINK and PARKIN collaborate to recruit ubiquitin to the surface of mitochondria and target them for mitophagy
- If the mitochondria get depolarised, PINK1 is recruited which activates PARKIN
What happens when PINK1 and/or PARKIN function is lost?
- Loose the ability to target damaged mitochondria for mitophagy so it starts to accumulate
- Accumulated damaged mitochondria work less efficiently so release more ROS and cause more cellular damage due to more protein misfolding
- Feedback loop generated- as soon as you accumulate damaged mitochondria, start to damage even more
Which steps of the autophagy pathway can be mutated and cause disruptions?
- Impairing autophagosome formation
- Disrupting cargo recognition
- Cause autophagic cargo
- Disrupting lysosomal formation
- Inhibits autolysosome formation
- Preventing secretion
What causes cancer?
Accumulation of damaged DNA
How is autophagy anti-oncogenic?
Before tumours have formed, autophagy is beneficial for cell homeostasis, damage removal, reducing ROS and inflammation
