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Cellular and Molecular > Lecture 22- Autophagy II > Flashcards

Lecture 22- Autophagy II Flashcards

1
Q

Describe the role of autophagy as a housekeeping process

A

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

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2
Q

What accumulates in cells lacking autophagy?

A

Protein aggregates

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3
Q

Why are neurons particularly sensitive to damage?

A

Because they are extremely long-lived cells, metabolically active and have long protrusions. This makes trafficking the proteins more difficult/less efficient

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4
Q

What does neuronal-specific autophagy disruption is mice cause?

A
  1. Accumulation of ubiquitinated aggregates

2. Increase apoptosis

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5
Q

How can apoptosis be viewed/studied?

A

Using TUNEL staining

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6
Q

What are proteinopathies?

A

Diseases where proteins are abnormally self-associating and aggregating due to confirmations changes

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7
Q

What proteinopathy causes Huntington’s disease?

A

Huntingin protein aggregates

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8
Q

What proteinopathy causes Alzheimer’s disease?

A

Amyloid-beta plaques aggregates

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9
Q

What proteinopathy causes Parkinson’s disease?

A

alpha-synclein aggregates

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10
Q

What is similar and different in the protein aggregates in Huntington’s, Alzheimer’s and Parkinson’s disease?

A

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

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11
Q

What causes Huntington’s disease?

A

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

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12
Q

Why does Huntington’s disease worsen with age?

A

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

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13
Q

What is the association of polyQ expansion and Huntington’s disease?

A

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

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14
Q

What are some mechanisms of toxicity?

A
  1. Loss of normal protein function
  2. Toxic oligomer
  3. Aggresomes themselves may be toxic
  4. Proteasomal damage
  5. Adaptor sequestration
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15
Q

What does the aggregation of alpha-synuclein cause in Parkinson’s disease?

A

Causes a loss of dopinergic neurons

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16
Q

How is alpha-synuclein protein normally degraded?

A
  1. By chaperone-mediated autophagy
  2. The LAMP2 receptor on the lysosome surface is able to recognise specific amino acid sequences/proteins
  3. These are then transported directly into the lysosome to be degraded
17
Q

How does alpha-synuclein mutations affect chaperone mediated autophagy?

A
  1. The A53T mutated alpha-synuclein blocks the CMA pathway
  2. The protein can still bind to the LAMP2 receptor but cannot be transported into the lysosome
  3. Therefore, mutated alpha-synuclein cannot be degraded, forms aggregates and causes toxicity
18
Q

How does damaged mitochondria link with Parkinson’s disease?

A
  1. Damaged mitochondria accumulate in Parkinson’s and are a big source of ROS
  2. ROS damages cellular components
  3. Therefore, Parkinson’s maybe caused by mitochondrial-derived oxidative damage
19
Q

What genes have been identified in familial Parkinson’s?

A

PINK1 and PARKIN genes

20
Q

How do PINK and PARKIN proteins normally function?

A
  1. PINK and PARKIN collaborate to recruit ubiquitin to the surface of mitochondria and target them for mitophagy
  2. If the mitochondria get depolarised, PINK1 is recruited which activates PARKIN
21
Q

What happens when PINK1 and/or PARKIN function is lost?

A
  1. Loose the ability to target damaged mitochondria for mitophagy so it starts to accumulate
  2. Accumulated damaged mitochondria work less efficiently so release more ROS and cause more cellular damage due to more protein misfolding
  3. Feedback loop generated- as soon as you accumulate damaged mitochondria, start to damage even more
22
Q

Which steps of the autophagy pathway can be mutated and cause disruptions?

A
  1. Impairing autophagosome formation
  2. Disrupting cargo recognition
  3. Cause autophagic cargo
  4. Disrupting lysosomal formation
  5. Inhibits autolysosome formation
  6. Preventing secretion
23
Q

What causes cancer?

A

Accumulation of damaged DNA

24
Q

How is autophagy anti-oncogenic?

A

Before tumours have formed, autophagy is beneficial for cell homeostasis, damage removal, reducing ROS and inflammation

25
Q

How is autophagy pro-oncogenic

A

After tumour formation, autophagy can help tumour survival during starvation and chemotherapy and prevent apoptosis

26
Q

What are 3 autophagy therapy strategies?

A
  1. Blocking survival to metabolic stress with autophagy inhibitors
  2. Inhibit autophagy to increase apoptosis during chemotherapy
  3. Elevate autophagy to remove damage and prevent cancer
27
Q

How does autophagy inhibit apoptosis?

A
  1. Beclin 1 forms a complex with vps24 and UVRAG which makes a PIP lipid on the ER
  2. This leads to the formation of the autophagosome
  3. Apoptosis is driven by membrane permeabilisation caspase activation which is activated by Bcl2
  4. Bcl2 and Beclin 1 directly interact with each other
  5. When you activate autophagy you move Bcl2 away from the mitochondria and inhibit apoptosis
  6. Therefore, autophagy promotes survival and inhibits apoptosis
  7. However, if you inhibit autophagy, you promote apoptosis and inhibit survival
28
Q

What was observed and confirmed during experiments on Beclin 1 mice mutants?

A

Beclin 1 mice mutants accumulate tumours and don’t survive compared to wildtypes

Demonstrating Beclin 1 is a tumour suppressor

Cellular and Molecular (24 decks)

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