Cell Death

Question 1

Causes of cell death

Answer 1

development
trauma
toxins
cerebral vascular disease
infectious agents
genetic diseases
neurodegenerative diseases (unknown causes)

Question 2

Multi-infarct dementia

Answer 2

cerebral vascular disease
after series of small strokes - appear asymptomatic (cumulative effect)
holes in the brain where the blood supply was reduced
additive effects over time

Question 3

Pick’s (frontotemporal degeneration)

Answer 3

widening of sulci and shrinking of gyri - classic effect of dementia
advanced degeneration causes the enlargening of ventricles

Question 4

Huntington’s Disease

Answer 4

disease of basal ganglia
ventricles are enlarged
caudate nucleus has shrunk from degeneration
attacks neurons

Question 5

Parkinson’s Disease

Answer 5

degeneration of substantia nigra
cell death of dopamine neurons - less melanin
brain stem

Question 6

Creutzfeldt-Jakob Disease

Answer 6

spongy form encephalopathy - prion disease (mad cow)
wide spread atrophy in entire brain, especially cortical region

Question 7

Meningioma

Answer 7

benign tumour growth in skull
headaches and tingling of arms/fingertips
occupies space and creates pressure on brain

Question 8

Ischemic stroke

Answer 8

lost consciousness
loss of movement in left arm and cannot speak
right side of brain - cell death caused contents to spill out and recruit inflammatory factors → growth = right hemisphere appears bigger than left

Question 9

Meningitis

Answer 9

infection of the meninges
presented with severe headache, nuchal rigidity and fever
puss-like substance coats surface of brain - cell lysis

Question 10

Alzheimer’s Disease

Answer 10

significant atrophy
lots of cell death leads to shrunken gyri and widened sulci

Question 11

Neurons

Answer 11

vulnerable cell
use glucose as energy source
not replaced in large numbers
brain consumes ~25% of total oxygen and glucose in blood

Question 12

Glial Cells

Answer 12

regulate health and cell survival in CNS
dysfunction → disease or injury of CNS

Question 13

Appropriate Cell Death

Answer 13

Developmental die off
programmed by DNA to establish the CNS
pruning excess cells and synapses = functional set
clean mode of cell death
apoptosis

Question 14

Inappropriate Cell Death

Answer 14

injury causes change to cells’ physiology/anatomy = disrupt homeostasis
can be reversible or irreversible - depending on frequency/intensity of stimulus
reversible injury will cause changes in cell that results in adaptation ex. closing ion channels

Question 15

Routes to Cell Death

Answer 15

energy failure; disturbance causing lack of oxygen/glucose to cell
- Glutamate-induced neuronal death
- reactive oxygen species
- hypoglycemia

Question 16

glutamate-induced neuronal death

Answer 16

excitotoxicity
over stimulation of glutamate → excessive release, failure of glutamate uptake, glutamate agonists
disruption of homeostasis - imbalance of ions (Ca2+, Na+)
cause both apoptosis and necrosis

Question 17

reactive oxygen species

Answer 17

damage cells - membranes and organelles
activate DNA programmed cell death = apoptosis

formation of free radicals - UV light, metabolism, inflammation, air pollution, smoking, ionizing radiation → DNA damage
substances: fried foods, alcohol, tobacco smoke, pesticides, air pollutants

Question 18

hypoglycemia

Answer 18

lack of glucose → depletion of cellular energy
activate apoptosis
ex. ischemia

Question 19

Ischemic cascade

Answer 19

ischemia reduces oxygen and glucose levels = decrease ATP (can produce reactive oxygen species and cause electron transport chain uncoupling → further decreases ATP)
low ATP → depolarization → neuron activation = glutamate (or other NT) release → influx of ions (Ca2+) → neuronal death

Question 20

Modes of inappropriate cell death

Answer 20

1. Necrosis
2. Apoptosis

Question 21

Necrosis

Answer 21

rapid, messy death → dramatic disintegration
exclusively when cell dies = irreversible process
marked dysregulation of ion homeostasis
swelling of cell and organelles

chromatin clumps; nuclear membrane is disrupted
ATP independent (no glucose → disruptions of ions)
no energy = gene transcription and protein synthesis stop; ion gradients disrupted; Ca2+ activates proteases
cells lyse → contents spilled into extracellular space → inflammatory response = possibly spread to other cells

Question 22

Proteases

Answer 22

degrade cellular components (normally held in lysosomes)

Question 23

Necrosis Cascade

Answer 23

necrosis initiating trigger (ex. excess glutamate) → targets Ca2+ stores = increased Ca2+ → activates Calpain → ruptures lysosome → release of proteases → degradation of cell, lysis

Question 24

triggers of cell death

Answer 24

apoptosis or necrosis is determined by intensity/duration of stimulus
very few triggers induce only one or the other

severe/sustained → necrosis
less severe/gradual transient stress → apoptosis

Question 25

Apoptosis

Answer 25

occurs in both appropriate and inappropriate cell death essential for development ex. removal of excess tissue in natal development of hands requires ATP has checkpoints at which process can be interrupted = reversible membrane remains intact - cell blebs → fragmentation and invagination pathways: intrinsic extrinsic caspase-independent

Question 26

intrinsic apoptosis

Answer 26

generated by signals arising within the cell (mitochondrial pathway) - conserved across species in the mitochondria, war between pro and anti-apoptotic factors - if pro factors win, they open a pore in the mitochondria that leaks cytochrome C → binds with APAF-1 to make apoptosome → recruits caspase-9 activation of caspase-3 (apoptosis executor)

Question 27

Bcl-2 family proteins

Answer 27

pro-apoptotic proteins: Bax, Bak, Bad, Bid anti-apoptotic proteins: Bcl-2, Bcl-xl, Bcl-w

Question 28

caspases

Answer 28

cytosine-dependent, aspartate-specific proteases apoptosis executors caspase-9: intrinsic caspase-8: extrinsic caspase-3: final executor

Question 29

extrinsic apoptosis

Answer 29

death receptor pathway triggered by death activators binding to receptors at the cell surface receptor is bound by ligand → recruits death domain → recruits caspase-8 to form DISC (death-induced signalling complex) → activation of caspase-8 → activates caspase-3 or caspase-7 = effector caspases

Question 30

Death receptors and ligands

Answer 30

Fas and TNF receptors are integral membrane proteins - receptor domains are exposed at surface of cell [Fas → FasL → FADD → caspase-8] [TNFR → TNFα → TRADD → casapse-8] death ligands are often surface bound on immune cells or secreted by immune cells

Question 30

Co-activation of extrinsic and intrinsic pathways

Answer 30

if death-inducing stimulus is strong enough: activation of caspase-8 in extrinsic pathway → cleave Bid (pro-apoptotic factor) to tBid (toxic) tBid: intracellular death signal to promote mitochondrial pore formation = activation of intrinsic pathway

Question 31

caspase-independent apoptosis

Answer 31

direct to DNA; triggered by reactive oxygen species signal to die (ROS) → AIF release from mitochondria (intermembrane space), migrates to cell nucleus and binds to DNA → triggers destruction of DNA and cell death AIF - apoptosis-inducing factor

Question 32

diseases associated with inhibition of apoptosis

Answer 32

cancer autoimmune disorders viral infections

Question 33

diseases associated with increased apoptosis

Answer 33

neurodegenerative disorders ischemic injury AIDS alcohol toxicity

Question 34

detection of apoptosis

Answer 34

cytomorphological changes DNA fragmentation → Tunel staining (incorporation of nucleotide labels into fragmented DNA - regular breaks) detection of caspases, cleaved substrates, regulators, and inhibitors → fluorescent dyes membrane alterations (intact or not = difference between apoptosis and necrosis) mitochondrial assays