Mechanisms of (neuronal) degeneration Flashcards
explain the 3 main forms of cell death
explain the basics of the pathways resulting in cell death
explain the differences in morphology between the mechanisms
what are the Methods of distinguishing between the forms of cell death
What are the 3 main forms of cell death and the 2 others
- Necrosis
- Apoptosis
- Autophagic death
others:
1. Ferroptosis
2. mitotic catastrophe
What are the morphological features of apoptosis
- rounding-up of the cell
- retraction of pseudopods
- Reduction of cellular and nuclear volume
- Nuclear fragmentation
- Minor modification of cytoplasmic organelles
- Plasma membrane blebbing
- Engulfment by resident phagocytes
What are the morphological features of autophagy
- Lack of chromatin condensation
- Massive vacuolization of cytoplasm
- Accumulation of (double-membraned) autophagic vacuoles
- Little or no uptake by phagocytes
What are the morphological features of Necrosis
- Cytoplasmic swelling (oncosis)
- rupture of plasma membrane
- Swelling of cytoplasmic organelles
- Moderate chromatin condensation
What is necrosis
- Necrosis is an accidental or pathological form of cell death resulting from irreversible damage directly following disease, injury and trauma.
- The pathological death of cells following injury usually involves degeneration of groups of contiguous cells in a region and often initiates an inflammatory response
- Mostly associated with physical cell damage, and ischemia
What are the cell changes in necrosis
Normal -> Cell swelling -> membrane break down -> release of cell contents
Explain apoptosis
- Apoptosis is an ordered cell death program. It is a spatially and temporally reproducible loss of large numbers of individual cells
- The program involves condensation of chromatin, ordered dismantling of the cell though activation of specific proteases and DNAses and cellular ‘blebbing’, .
- No inflammation is involved in the initiation of apoptosis.
What are the cell changes in apoptosis
normal -> cell shrinkage and chromatin condensation -> DNA/Nuclear fragmentation and membrane blebbing -> apoptotic bodies
Explain Autophagocytosis
- Lack of chromatin condensation
- Massive vacuolization of the cytoplasm
- Accumulation of (double-membraned) autophagic vacuoles
- Little or no uptake by phagocytic cells, in vivo
- BUT also a cell survival mechanism for large protein or mitochondrial turnover
What happens when a cell dies by apoptosis?
- Activation of “death” receptor pathways
- Membrane alterations – proteins on the inside of the membrane (like phosphatidylserines) translocate to the outside of the cell.
- Initiation of protein cascades (pro-caspases)
- Mitochondrial changes- mitochondrial permeability is altered releasing protease activators – cytochrome C is released into the cytosol.
- DNA fragmentation - irreversible, commits cell to die. May be caused by Ca2+ and Mg2+ dependent nuclear endonuclease – an enzyme that cleaves DNA
What are the molecular events occurring during apoptosis
*Death receptors e.g. p75NTR, Fas, TNFR
*Mediating components e.g. Apoptotic protease-activating factor1 (Apaf-1), Fas associated death domain protein (FADD), K+ efflux, JNK, Bax
*Anti-apoptotic proteins e.g. Bcl-2 family, Inhibitor of apoptosis proteins (IAPs/BRIPs)
* Cysteine protease Caspase family
What do the Proteins of Bcl-2 family in apoptosis consist of
The Bcl-2 family has a crucial role in intracellular apoptotic signal transduction. It consists of anti-apoptotic (Bcl-2 and Bcl-XL) and pro-apoptotic (Bax) proteins.
What is Bcl-2 apoptosis
Bcl-2 is high in the CNS during development but down regulated after birth. It is crucial for the maintenance of neuronal survival.
what is Bcl-Xl in apoptosis
Bcl-2 is high in the CNS during development but down regulated after birth. It is crucial for the maintenance of neuronal survival.
what is Bax in apoptosis
Bax is widely expressed in the nervous system. Its activation is a crucial event for neuronal cell death induced by trophic factor withdrawal as well as that which occurs following injury.
explain The mitochondrial apoptotic pathway
- Stimulus:
- DNA damage
- Growth factor deprivation
-Endoplasmic reticulum stress - Proapoptotic Bcl2-family proteins
- MOMP releases apoptotic factors
- Apoptosome
- cytochrome c
- Caspase-9 - Activation of effector caspases by cleavage
- Apoptotic cell death
Explain apoptosome
Explain Apoptotic protease-activating factor1 (Apaf-1)
- Apaf-1 is a cytoplasmic protein that initiates apoptosis.
- It contains several copies of the WD-40 domain (inhibits Apaf-1 self-association), a caspase recruitment domain (CARD), and an ATPase domain (NB-ARC).
- Upon binding cytochrome c and dATP, Apaf-1 forms an apoptosome. The apoptosome binds and cleaves pro-caspase 9, releasing its mature, activated form. Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.
What are the central regulators of apoptosis
Caspases
What are some inhibitors of cell death
Other Anti-apoptotic mechanisms
* Growth factors: Neurotrophins and Cytokines = Pro-survival
* Akt and kinases that regulate cell death mediators (eg Bax)
* IAP- Inhibitors of apoptosis (inhibit caspases)
