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NEURO 210 > Lecture 14: Cell Death > Flashcards

Lecture 14: Cell Death Flashcards

1
Q

What are the many different causes of cell death?

A

development
trauma
toxins (e.g. alcohol, pesticides, heavy metals)
cerebral vascular disease (ischemic/hemorrhagic stroke)
infectious agents
genetic diseases
neurodegenerative diseases of unknown cause

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2
Q

Where does Pick’s disease cause cell death?

A

a cause of frontotemporal degeneration

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3
Q

Where does Huntington’s disease cause cell death?

A

basal ganglia

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4
Q

Where does Parkinson’s disease cause cell death?

A

damage to neurons that contain melanin

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5
Q

Where does advanced CJD cause cell death?

A

“mad cow” disease

brain starts to look like a sponge

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6
Q

Where does meningioma cause cell death?

A

tumor in the meninges

headaches, tingling in fingers

creates pressure on the brain, indentation

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7
Q

What are the two types of cells in the CNS?

A

neurons and glial cells

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8
Q

What are neurons?

A

much more valuable type of cell - live on the edge

brain consumes ~25% of total oxygen and glucose in the bloodstream (as high as 50% if required)

neurons use glucose as their primary carbon source

neurons are not replaced in significant numbers

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9
Q

What are glial cells?

A

regulate health and cell survival in the CNS

dysfunction implicated in disease and injury to CNS

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10
Q

What is “appropriate” cell dealth?

A

during development more neurons than will be needed are born

gradually “prune off” unused cells

fine tuning connections orchestrated by interactions with the environment (macro and microenvironments)

developmental cell death occurs without tissue inflammation or disruption of surrounding cells

“use it or lose it” principle that involves growth factors and electrophysiological activity

this type of cell death is programmed by the DNA for establishment of the central nervous system and is therefore considered “appropriate”

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11
Q

What is an example of non-programmed necrosis?

A

non-programmed cell death

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12
Q

What are examples of programmed apoptotic cell death?

A

apoptosis

anoikis

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13
Q

What state is a normal cell in?

A

normal cell is in a steady state or homeostasis

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14
Q

What is injury to the cell?

A

injury is any stimulus bringing changes in cell physiology and/or anatomy - either internal or external

injury can be either reversible or irreversible

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15
Q

What does reversible injury lead to?

A

adaptation results from the changes in a cell due to reversible injury

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16
Q

What does irreversible injury lead to?

A

irreversible injury results in cell death

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17
Q

What are the initial characteristics of cell death?

A

energy failure

disturbance causing lack of oxygen or glucose to cell

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18
Q

What is glutamate-induced neuronal death?

A

“excitotoxicity”

over stimulation of glutamate activity

excessive stimulation through receptors for neurotransmitter glutamate

caused by excessive release, failure of glutamate uptake mechanisms, exposure to drugs or poison that act just like glutamate (agonist)

too much glutamate activity causes an imbalance of other ions such as calcium and sodium which can result in cell death (messes up homeostatic activity)

will cause both DNS programmed and necrotic cell death

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19
Q

What are reactive oxygen species?

A

free radicals

will damage cell membranes and intracellular organelles

bounce around and cause damage

will activate DNA programmed cell death mechanisms

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20
Q

What is hypoglycemia?

A

loss of glucose leads to rapid depletion of cellular energy reserves

will activate DNA programmed cell death mechanisms

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21
Q

What are the many events that can lead to the formation of free radicals?

A

UV light

ionizing radiation

smoking

air pollution

inflammation

metabolism

22
Q

What are some examples of free radical generating substances?

A

fried foods

alcohol

tobacco smoke

pesticides

air pollutants

23
Q

What are the two main modes of “inappropriate” cell death?

A

necrosis: rapid, somewhat messy death

apoptosis: programmed cellular suicide

24
Q

What is necrosis?

A

dramatic and very rapid form of cell death in which every compartment of the cell disintegrates

messy, cells rupture and spit out intracellular components

during necrotic death process, chromatin clumps and nuclear membrane is disrupted

gene transcription and protein synthesis stops

25
Q

What does the marked dysregulation of ion homeostasis cause in cells undergoing necrosis?

A

cell swelling

dilation of mitochondria and ER

formation of vacuoles in cytoplasm

activation of enzymes called proteases, which degrade cellular components

normally these proteases are held in packages (lysosomes) but necrotic processes release them

26
Q

Why is ATP rapidly depleted in necrosis?

A

no energy means that ion (Na+, Cl-, Ca++) gradients disrupted

Ca++ activates proteases (calpains and cathepsins) the digest cell

27
Q

What happens when cells lyse and spill their contents in necrosis?

A

can be damaging (e.g. glutamate)

can cause inflammatory response

28
Q

What are the steps of necrosis?

A
  1. necrosis initiating insults enter the cell
  2. Cause calcium stores in the ER to release Ca++, which causes an increase
  3. Ca++ activates calpain
  4. Calpain triggers lysosome rupture
  5. Lysosome rupture causes the digestive enzyme cathepsin to be released
  6. Cathepsin causes cell death
29
Q

What are the triggers of cell death?

A

there are very few death triggers that are only capable of inducing only necrosis or apoptosis

whether a cell undergoes apoptosis or necrosis is determined primarily by the intensity and/or duration of the death-inducing stimulus

30
Q

How does the severity of the trigger determine which type of cell death occurs?

A

if stimulus is severe and/or sustained it will induce necrosis

if stimulus less severe with transient stresses, it will induce apoptosis

e.g. glutamate/excitotoxicity, trauma, energy failure/ischemia can vary in intensity and duration

31
Q

What is apoptosis?

A

there are multiple forms of programmed cell death (PCD) but apoptosis is the best characterized form of PCD

apoptosis occurs in both :appropriate” and inappropriate” cell death

essential for development (e.g. in fetuses, apoptosis gets rid of webbing between fingers)

32
Q

What is the intrinsic pathway in apoptosis?

A

generated by signals arising within the cell

aka mitochondrial pathway

pathway is largely conserved from worms to mammals

33
Q

What is the extrinsic pathway in apoptosis?

A

triggered by death activators binding to receptors at the cell surface

aka the death receptor pathway

34
Q

What is the caspase-independent pathway in apoptosis?

A

direct to DNA

triggered by reactive oxygen species

through apoptosis-inducing-factor (AIF)

AIF normally located in intermembrane space of mitochrondria

35
Q

How is the intrinsic pathway involved in the interplay of a family of proteins?

A

some members of this family will act to prevent apoptosis (anti-apoptotic) and some will act to promote apoptosis (pro-apoptotic)

the anti-apoptotic family is referred to as the Bcl-2 family (B cell leukemia/lymphoma 2)

once the interplay within Bcl-2 family members is complete and if the pro-apoptotic members won the “war”, the program continues through the activation of the program executors (the caspases)

36
Q

What are the pro-apoptotic proteins?

A

Bax, Bak, Bad, Bid

start getting released if triggered and if you have enough ATP

37
Q

What are the anti-apoptotic proteins?

A

Bcl-2, Bcl-XL, Bcl-W

if they win the progress is stopped

38
Q

What are the steps of apoptosis through the intrinsic pathway?

A

the pro-apoptotic “winner” causes a pore to open in the mitochondria

out out of the pore leaks cytochrome c (amongst other compounds)

cytochrome c binds with a molecule called apoptosis activating factor-1 (APAF-1) and induced it to create the first stage of an apoptosome

together APAF-1 and cytochrome c capture and bind caspase-9 which completes the apoptosome

if nothing stopes he program at this stage, the apoptosome will progress to the next step, activation of the final apoptosis executor: caspase 3

39
Q

What is the function of death receptors?

A

Fas and TNF receptors are integral membrane proteins with receptor domains exposed at surface of cell

death ligands are often surface bound on immune cells (e.g. microglia and T-cells), or secreted by immune cells

40
Q

What is the Fas receptor?

A

Fas is bound by trimeric Fas ligand (FasL)

this causes recruitment of FADD through Fas’s death domain (DD)

41
Q

What are the steps of apoptosis through the extrinsic pathway?

A
  1. FADD recruits casapse-8 through FADD’s death effector domain to form the death-induced signaling complex (DISC), it is made up of FasR, FADD, and caspase-8
  2. the binding of FADD and casapse-8 causes activation of the caspase-8 and subsequent activation of effector caspase such as caspase 3 or 7
  3. the extrinsic pathway interacts with the intrinsic pathway via caspase-8 cleavage of BID to produce tBID
  4. death receptors relay extracellular ligand binding to intracellular activation caspase 8
42
Q

How are the intrinsic and extrinsic pathways co-activated?

A

extrsinic and intrinsic pathways can interact via caspase-8 cleavage of Bid to tBid

tBid functions as an intracellular death signal to promote mitochondrial pore formation

extrinsic and intrinsic pathways can thus be co-activated

43
Q

What are the steps of apoptosis through the caspase-independent pathway?

A
  1. cell receives signal to die (e.g. ROS)
  2. AIF released from mitochondria
  3. migrates to cell nucleus
  4. binds to DNA
  5. triggers destruction of DNA and cell death
44
Q

What are the differences between apoptosis and necrosis?

A

two processes are temporally dislocated and likely to represent two extremes of a continuum

necrosis process can start only and exclusively when the cell dies and is an irreversible process - no return

apoptosis has a number of checkpoints at which the process can be interrupted -recoverable

45
Q

What are the key characteristics of apoptosis?

A

cell size: shrinkage and fragmentation

cell membrane: blebbed, membrane integrity maintained

mitochondria: increased membrane permeability, structurally okay

nuclei: chromatin is clumped and fragmented

DNA degradation: fragmented, DNA appears in cytosol

Process: DNA programmed cascade, requires protein synthesis, requires RNA transcription, requires ATP

Inducing stimuli: developmental programs, disease processes

46
Q

What are the key characteristics of necrosis?

A

cell size: swells

cell membrane: smoothing of membrane, lysis of membrane

mitochondria: swells, disordered structure

nuclei: swells, membrane disrupted

DNA degradation: diffuse random

process: no protein synthesis, no RNA transcription, energy independent, ATP depletion

inducing stimuli: disease processes

47
Q

What are diseases associated with the inhibition of apoptosis?

A

cancer: follicular lymphomas, carcinomas with p53 mutations, hormone-dependent tumors, breast, ovarian, and prostate cancer

autoimmune disorders: systemic lupus erythematosus, immune-mediated glomerulonephritis

viral infections: herpesviruses, poxvirus, adenoviruses

48
Q

What are diseases associated with increased apoptosis?

A

neurodegenerative disorders: Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, retinitis pigmentosa

ischemic injury: stroke, myocardial infarction, reperfusion injru

AIDS

toxic-induced liver disease (alcohol)

49
Q

How do we detect apoptosis?

A

cytomorphological changes

DNA fragmentation

detection of caspases, cleaved substrates, regulators and inhibitors

membrane alterations

mitochondrial assays: is there a pore? has cytochrome c been released?

50
Q

How is apoptosis detected in images?

A

blebbing of cell membranes

condensation of chromatin

nuclear fragmentation

increased permeability

51
Q

What is Tunel staining?

A

terminal deoxynucleotidyl transferase mediated dUTP nick end of labeling

allows incorporation of nucleotide labels into fragmented DNA

NEURO 210 (23 decks)

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