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Cell and molecular extras > Lecture 22 Autophagy 2 > Flashcards

Lecture 22 Autophagy 2 Flashcards

1
Q

Autophagy is what kind of process?

A

A housekeeping process

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2
Q

What occurs with no autophagy?

A

Protein aggregates

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3
Q

Which cell is particularly sensitive to autophagy?

A

Neurons

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4
Q

Neuronal-specific autophagy in mice causes?

A

Accumulation of ubiquinated aggregates

Increased apoptosis

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5
Q

What occurs to the autophagic capacity of cells as we age and this causes?

A

Decreases so ability to get rid of damage decreases until cells apoptose

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6
Q

Name 3 proteinopathies in neurodegeneration?

What protein aggregates form in these diseases?

A
  • α-synuclein in Parkinsons
  • Huntingin aggregates in Huntington’s
  • Amyloid β plaques in Alzheimer’s
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7
Q

What is Huntingtons caused by?

A
  • Mutation in a single gene – monogenic disease

* Caused by polyglutamine (polyQ) expansion in Huntingtin protein

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8
Q

Number of Q in healthy Huntington protein vs mutant

A

• Q<18 = healthy, Q>35=disease-causing

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9
Q

What occurs as a result of an expanded polyQ Huntington protein?

A
  1. Huntington protein is misfolded
  2. N terminus of the protein gets cleaved so proteins oligomerise and aggregate
  3. Leads to ubiquitination
  4. Causes proteasomal degradation
    OR aggresome formation and then autophagic degradation
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10
Q

Where in this Huntington pathway is toxic?

A

It is unclear

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11
Q

Name ways toxicity is caused in Huntington pathway:

A
  • Loss of normal function of Huntingtin
  • Toxic oligomers
  • Proteasomal damage
  • Aggresomes
  • Aggresomes sequester adaptor proteins
  • Protein endogenously binding to Huntingin
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12
Q

How many people does Parkinson’s affect?

A

1-2 per 100 in UK

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13
Q

Parkinsons is due to loss of what?

A

Dopaminergic neruons

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14
Q

Main neuropathology of Parkinsons is?

A

• Main neuropathology is aggregates of α-synuclein (Lewy Bodies)

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15
Q

Describe the genetics of Parkinsons?

A

• Complex genetics

  • Only 5-10% of cases familial (i.e. clear genetic pathway)
  • α-synuclein itself rarely mutated
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16
Q

How often is α-synuclein itself mutated

A

Rarely

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17
Q

What normally degrades α-synuclein?

A

Chaperone-mediated autophagy

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18
Q

How does chaperone mediated autophagy work in Parkinsons?

A
  • LAMP2 receptor on surface of lysosome directly recognises α-synuclein and is transported into the lysosome to be degraded.
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19
Q

Example of mutated α-synuclein?

A

A53T

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20
Q

What do mutated versions of α-synuclein do?

A

Block the chaperone-mediated pathway, causing toxicity. They are recongised but clog LAMP2 stopping other proteins being degraded too

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21
Q

What else accumulates in Parkinsons?

A

Damaged mitochondria

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22
Q

What are mitochondria the main source of?

A

Reactive Oxygen Species (ROS)

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23
Q

What does ROS do?

A

Damages cellular components

24
Q

What is the hypothesis for mitochondrial disfunction in parkinsons?

A

Parkinsons may be caused by mitochondrial-derived oxidative damage

25
Q

What 2 genes regulate mitophagy

A

PINK1

PARKIN

26
Q

What is PINK1?

A

A mitochondrial kinase that phosphorylates damaged mitochondria in the PINK1/PARKIN mediated mitophagy

27
Q

What is PARKIN?

A

Cytosolic E3 ubiquitin ligase that protects cells against death and dopaminergic degeneration

28
Q

What sort of mutation occurs in PINK1?

A

Loss of function in 5-10% sporadic earl-onset Pakrinsons

29
Q

What mutation occurs in PARKIN?

A

Mutated in 50% of autosomal recessive

10-15% sporadic early-onset Parkinson’s

30
Q

Describe the normal pathway in mitophagy?

A
  1. Depolarised mitochondria
  2. PINK1 and so PARKIN recruited
  3. Ubiquitination of mitochondria
  4. Degradation by mitophagy
31
Q

Mutation in PINK1/PARKIN effect?

A
  • Less ubiquitination
  • Accumlation of damaged mitochondira
  • Lots of ROS made
  • Oxidative damage
  • Protein misfolding
  • Damaged organelles
  • Increase in DNA damage and damage of other proteins and mitochondria
  • Vicous cycle
32
Q

How many mechanisms are there for neurodegeneration?

A

Many

33
Q

What are the mechanisms for neurodegeneration?

A

Anything affecting trafficking/ability of phagosome to fuse/make a lysosome can predispose you to these conditions.

34
Q

Do you need a mutation in the protein aggregate for it to accumulate?

A

No

35
Q

Examples of the mechanisms involved in neurodegeration:

A 
Impaired autophagosome formation 
Disrupted lysosomal function 
Secretion 
Inhibited autolysosome formation 
Autophagic cargo 
Disruption of cargo recognition
36
Q

How is cancer caused? Plus examples

A

Accumulation of DNA damage

• cellular metabolism, UV light, Ionising radiation, chemical exposure, replication errors

37
Q

Response to cancer?

A

• Response: Cell cycle checkpoint activation, transcriptional programme activation, DNA repair (direct removal, base excision repair, nucleotide excision repair, ds break repair (HR/NHEJ), apoptosis

38
Q

Is autophagy tumour suppressive or pro-oncogenic?

A

Both

39
Q

Describe how autophagy is tumours suppressive?

A

Autophagy ↓ in damaged organelles ↓ protein toxicity ↓ ROS

And so autophagy inhibits oxidative stress/DNA damage/tumourigenesis

40
Q

What causes DNA damage accumulation?

A

Beclin1 (Atg6)

41
Q

How often is beclin1 mutated?

A

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

42
Q

What occurs in Beclin+/- mice?

A

They cannot do as much autophagy so accumulate damage and tumours

43
Q

How is autophagy pro-oncgenic?

A

• Autophagy is unregulated in hypoxic, nutrient-poor tumour regions.

44
Q

What would blocking autophagy occur in the pro-oncogenic autophagy?

A

Necrosis or apoptosis suggesting autophagy keeps the cells alive in this tumour region

45
Q

Does autophagy inhibit apoptosis?

A

yes

46
Q

How does autophagy inhibit or induce apoptosis?

A
  • Pro-survival: The complex compromising of Beclin1 makes PIP3 on the subdomain of the ER which is used to make the autophagosome. Activity of Beclin1 will promote autophagosome formation. Autophagy is pro-survival.
  • Pro-death: In contrast apoptosis can be pro-death due to Bcl2 etc. which localise on the surface of mitochondria and cause mitochondria permeabilization and initiate caspases. This causes apoptosis.
47
Q

Pro-survival

A

Beclin1
PIP3
Autophagosomes

48
Q

Pro-death

A

Bcl2 surface of mitochondria
Permeabilisation
Caspases
Apoptosis

49
Q

How do Bcl2 and Beclin1 interact?

A

Directly e.g. Pro-survival pathways will sequester Bcl2 from the mitochondria to repress apoptosis, hence activating autophagy decreases apoptosis and vice versa

50
Q

What does inhibiting apoptosis drive?

A

Tumour survival and chemotherapy resistance

51
Q

When do you want to increase autophagy?

A

Neurodegenerative diseases

52
Q

When and why do you want to decrease autophagy?

A

Cancer – increasing autophagy means less likely to apoptose, so drive tumour survival and chemotherapy resistance

53
Q

Name the three strategies for autophagy therapeutics?

A
  • Block survival to metabolic stress with autophagy inhibitors
  • Inhibit autophagy to increase apoptosis during chemotherapy
  • Elevate autophagy to remove damage and prevent cancer
54
Q

How is autophagy anti-oncogenic?

A
  • Cell homeostasis
  • Damage removal
  • Reduced ROS/genotoxicity
  • Reducing inflammation
55
Q

How is autophagy pro-oncogenic?

A
  • Survival during oxygen of nutrient hortage
  • Prevention of apoptosis
  • Survival during chemotherapy

Cell and molecular extras (16 decks)

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