Cell Death Flashcards
Causes of cell death
development
trauma
toxins
cerebral vascular disease
infectious agents
genetic diseases
neurodegenerative diseases (unknown causes)
Multi-infarct dementia
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
Pick’s (frontotemporal degeneration)
widening of sulci and shrinking of gyri - classic effect of dementia
advanced degeneration causes the enlargening of ventricles
Huntington’s Disease
disease of basal ganglia
ventricles are enlarged
caudate nucleus has shrunk from degeneration
attacks neurons
Parkinson’s Disease
degeneration of substantia nigra
cell death of dopamine neurons - less melanin
brain stem
Creutzfeldt-Jakob Disease
spongy form encephalopathy - prion disease (mad cow)
wide spread atrophy in entire brain, especially cortical region
Meningioma
benign tumour growth in skull
headaches and tingling of arms/fingertips
occupies space and creates pressure on brain
Ischemic stroke
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
Meningitis
infection of the meninges
presented with severe headache, nuchal rigidity and fever
puss-like substance coats surface of brain - cell lysis
Alzheimer’s Disease
significant atrophy
lots of cell death leads to shrunken gyri and widened sulci
Neurons
vulnerable cell
use glucose as energy source
not replaced in large numbers
brain consumes ~25% of total oxygen and glucose in blood
Glial Cells
regulate health and cell survival in CNS
dysfunction → disease or injury of CNS
Appropriate Cell Death
Developmental die off
programmed by DNA to establish the CNS
pruning excess cells and synapses = functional set
clean mode of cell death
apoptosis
Inappropriate Cell Death
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
Routes to Cell Death
energy failure; disturbance causing lack of oxygen/glucose to cell
- Glutamate-induced neuronal death
- reactive oxygen species
- hypoglycemia
glutamate-induced neuronal death
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
reactive oxygen species
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
hypoglycemia
lack of glucose → depletion of cellular energy
activate apoptosis
ex. ischemia
Ischemic cascade
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
Modes of inappropriate cell death
- Necrosis
- Apoptosis
Necrosis
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
Proteases
degrade cellular components (normally held in lysosomes)
Necrosis Cascade
necrosis initiating trigger (ex. excess glutamate) → targets Ca2+ stores = increased Ca2+ → activates Calpain → ruptures lysosome → release of proteases → degradation of cell, lysis
triggers of cell death
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
Apoptosis
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
intrinsic apoptosis
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)
Bcl-2 family proteins
pro-apoptotic proteins: Bax, Bak, Bad, Bid
anti-apoptotic proteins: Bcl-2, Bcl-xl, Bcl-w
caspases
cytosine-dependent, aspartate-specific proteases
apoptosis executors
caspase-9: intrinsic
caspase-8: extrinsic
caspase-3: final executor
extrinsic apoptosis
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
Death receptors and ligands
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
Co-activation of extrinsic and intrinsic pathways
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
caspase-independent apoptosis
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
diseases associated with inhibition of apoptosis
cancer
autoimmune disorders
viral infections
diseases associated with increased apoptosis
neurodegenerative disorders
ischemic injury
AIDS
alcohol toxicity
detection of apoptosis
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
