#15 Cell Death Flashcards
What are the primary cells of the CNS?
- Neurons: very vulnerable, brain consumes about 25-50% of total oxygen and glucose in the bloodstream, neurons use glucose as their primary carbon source, neurons are not replaced insignificant
- Glial cells: regulate the health and cell survival in the CNS, dysfunction implicated in disease and injury to the CNS
What is appropriate cell death?
Developmental die-off
During development more neurons than needed are born, thus fine tuning of connections orchestrated by interactions with the environment is necessary
Developmental cell death occurs without tissue inflammation or disruption of other cells
Uses the “use it or lose it” principle involving growth factors and electrophysiological change
This type of cell death is programmed in DNA for establishment of the central nervous system.
What is inappropriate cell death?
Injury is any stimulus bringing changes in cell physiology and/or anatomy and can be either internal or external.
This injury can be either reversible or irreversible. Adaptation results from reversible cell death, and cell death results from irreversible cell death
What are the three common routes of cell death?
Glutamate induced neuronal death, reactive oxygen species, hypoglycemia
What is glutamate induced neuronal death?
Excitotoxicity, excessive stimulation through receptors for neurotransmitter glutamate
Caused by excessive release, failure of glutamate uptake mechanisms, exposure to drugs/poisons that act like glutamate
Too much glutamate causes an imbalance of other ions such as calcium and sodium resulting in cell death
Will cause both DNA regulated/programmed and necrotic death
How do cells die from ROS and hypoglycemia?
ROS: damages cell membranes and intracellular organelles, and will activate DNA programmed cell death mechanisms.
Hypoglycemia: loss of glucose leads to rapid depletion of cellular energy reserves, and will activate DNA programmed cell death.
What is the ischemic cascade of events?
Ischemia
No oxygen and glucose
No ATP
Depolarization
Glutamate release
NMDA receptor activation
Increase Ca+
Neuronal injury or death
What are the two main modes of cell death in inappropriate cell death? What determines which mode is used?
- Necrosis: rapid, somewhat messy, swelling
- Apoptosis: programmed cellular suicide
Determined by frequency and strength of stimulus
What is necrosis?
Type of inappropriate cell death
Dramatic and very rapid, every compartment of the cell disintegrates
Characterized by: cell swelling, dilation of mitochondria and ER, formation of vacuoles, activation of proteases which degrade cellular components (normally held in lysosomes to prevent them breaking things down)
Chromatin clumps and nuclear membrane is disrupted, gene transcription and protein synthesis stops, ATP is depleted therefore no energy and calcium proteases activate which digest cells, the cells lyse and spill their contents into extracellular space causing inflammatory response
What are some triggers of cell death?
Few triggers that only induce necrosis or apoptosis, most trigger both. Whether a cell undergoes apoptosis or necrosis is determined by the intensity/duration of the death inducing stimulus.
If stimulus is severe and or sustained, it will induce necrosis. If the stimulus is less severe and transient it induces apoptosis
TRUE OR FALSE: Apoptosis is in both the appropriate and inappropriate cell death pathways
TRUE
What are the three pathways involved in apoptosis?
Intrinsic: generated by signals arising from within the cell
Extrinsic: triggered by death activators binding to receptors at the cell surface
Caspase independent pathway triggered by ROS
What happens in the intrinsic pathway? What is the other name for this pathway?
Mitochondrial pathway
Conserved from worms to mammals
Involves a family of proteins, some of which are apoptotic and anti-apoptotic. This is the Bcl-2 family. Once the interplay between these proteins is complete and the pro-apoptotic proteins won (Bax, Bad) the program continues through caspases
A pore opens in the mitochondria and leaks cytochrome C into the cytoplasm. This binds with apoptosis activating factor 1 (APAF-1) to create the initial apoptosome, and then these bind caspase 9 to complete the apoptosome. If nothing stops the program at this stage then the apoptosome activates caspase 3(apoptotic excecuter)
What is the extrinsic pathway? What is the other name for this pathway?
Death receptor pathway.
Involves the FasL/FasR as well as TNF alpha/TNFR1.
Fas and TNF are integral membrane proteins with their receptor domains exposed at cell surface. The FasR is bound by FasL which recruits the FADD (death domain).FADD recruits caspase 8 and forms death-induced signalling complex (DISC)
After FADD binds and activates capsase 8 there is activation of the effector caspase 3 or 7
How do the intrinsic or extrinsic pathway interact?
They interact via caspase 8 cleavage of BID to produce tBID
tBID functions as an intracellular death signal to promote mitochondrial pore formation. Thus both pathways can be coactivated
