Neuropathology Flashcards
(45 cards)
Describe the differences of necrosis and apoptosis:
Necrosis is cell murder (physical or chemical injury from which the cell cannot recover).
Apoptosis is cell suicide (self-destruct programme, active process requiring energy and sometimes new gene expression).
Distinguished by different biochemical and morphological characteristics.
List the properties of necrosis:
Sudden, severe death Passive process - no energy required Membrane disintegrates and cell becomes leaky Cell and organelle swelling Dispersal of chromatin and random DNA fragmentation Cell lysis Inflammatory response No new gene expression
List the properties of apoptosis:
Subtle, slowly evolving cell death Active process - energy required Membrane blebbing Cell shrinks, organelles remain intact Chromatin condenses, internucleosomal DNA fragmentation (regular 180 bp pattern) Apoptotic bodies engulfed by phagocytes No inflammatory response New gene expression often required
Describe why apoptosis is important:
Important for morphogenesis of embyronic tissue
Physiological mechanism for regulation of cell numbers - homeostasis of adult organs and tissues
Eliminates cells that are damaged, infected or in the wrong place
Describe the importance of neuronal apoptosis:
Neuronal apoptosis is important for development of the CNS and PNS.
Approximately half the neurons generated in the mammalian nervous system are removed by apoptosis during development
Describe how deregulated apoptosis causes disease:
Too much or too little apoptosis can be catastrophic.
Too much apoptosis contributes to neurodegerative disorders e.g. Alzheimer’s disease where nerve cells die by an apoptotic mechanism.
Not enough apoptosis can lead to cancer.
Describe the basics of how apoptosis works:
Death signals activate caspase enzymes.
Caspases dismantle the cell and generate the calssical apoptotic morphology.
Describe caspase enzymes:
Family of 14 cysteine aspartate-specific proteases that have a cysteine residue in the active site and cleave target proteins after an aspartate residue.
Exist in cells as inactive pro-enzymes or zymogens.
Activated by cleavage in response to specific cell stressors leading to cell suicide by apoptosis.
Caspases 2, 3, 6-10 as involved in apoptosis (the rest inflammation).
Describe the discovery of the caspase enzymes:
Discovered based on homology with CED-3 in the nematode C.elegans. Cell number is precisely regulated in C.elegans. Blocking CED-3 prevents cells from dying.
Caspase-3 is the mammalian equivalent which promotes apoptotic death. KO mice have bigger brains and can’t prune down neurons.
Describe the pathways of caspase activation:
2 main pathways:
1. Extrinsic/death receptor pathway
2. Intrinsic/mitochondrial pathway
Also a third pathway involving the ER
Describe the extrinsic death receptor pathway:
Fas ligand binds to cell surface death receptor
Receptor association and recruitment of cytosolic adaptor protein FADD through death domain
DED of FADD binds to DED of procaspase-8 (or 10)
Cleavage and activation of caspase-8
Cleavage and activation of caspase-3,6,7
Cleavage of caspase substrates and generation of apoptotic morphology
Describe the intrinsic mitochondria pathway:
Response to DNA damage and p53 activation
Cytochrome c released into cytoplasm
Interaction of cytochrome c, Apar-1 and procaspase-9 to form the apoptosome
Cleavage and activation of caspase-9
Cleavage and activation of caspase-3,6,7
Cleavage of caspase substrates and generation of apoptotic morphology
Describe the endoplasmic reticulum pathway:
Response to protein misfolding and ER stress
Cleavage and activation of caspase-12
Cleavage and activation of caspase-9 followed by caspases-3,6,7
Cleavage of caspase substrates and generation of apoptotic morphology
Describe caspase substrates:
Caspase mediated cleavage of:
- PARP inactivates DNA repair
- ICAD allows nuclear translocation of CAD and internucleosomal DNA fragmentation
- Lamins results in nuclear shrinkage
- Fodrin and Actin results in reorganisation of the cytoskeleton
- Bid by caspase 8 through the death receptor pathway allows mitochondrial release of cytochrome c and activation of mitochondrial apoptotic pathway
Describe caspase-independent apoptosis:
Cells grown in culture undergo apoptosis in the presence of pan caspase inhibitor Z-VAD.fmk.
This suggests caspase-independent mechanisms which also lead to apoptotic cell death, such as necroptosis, a regulated form of necrotic death.
Describe the role of anti-apoptotic molecules:
Prevent unwanted caspase activation.
Describe anti-apoptotic molecules in the mitochondrial pathway:
Bcl-2 and Bcl-XI prevent cytochrome c release. Inhibit channel formation in the outer membrane by sequestering pore-forming pro-apoptotic proteins e.g. Bax and Bak.
Describe anti-apoptotic molecules in the death receptor pathway:
FLIP family contain DED regions and compete with caspase-8 and 10 for binding to death receptors.
Describe the inhibitors of apoptosis proteins (IAPs):
Endogenous caspase inhibitors (XIAP, NIAP, cIAP-1, cIAP-2, livin, survivin).
Bind to active caspase enzymes (3,7,9). Prevent substrate entry into caspase active site and promote ubiquitination and proteasomal degradation. Inhibited by Smac/DIABLO released from mitochondria intermembrane space with cytochrome c. Therefore apoptosis is regulated by activation of death proteins (caspases) and inactivation of survival proteins.
Describe brain damage:
Nerve cell death.
Results from acute (trauma, stroke, concussion) or chronic (neurodegenerative) injuries.
Injury disrupts normal glutamate neurotransmission.
Define excitotoxicity:
Prolonged or excessive activation of glutamate receptors kills neurons.
Describe the normal functions of glutamate:
Main excitotory neurotransmitter in the brain, diverse functions including learning, memory, movement and sensation.
Describe the types of glutamate receptors:
Iontropic (NMDA and AMPA/Kainate)
Metabotrophic (I, II, III)
Describe the action of NMDA receptors:
Depolarisation (remove Mg2+) + glutamate + glycine (agonists)
Opens channel (permeable to calcium)
Influx of calcium
Depolarisation of neuron
