Cell death (DONE) Flashcards
Cell types in the CNS
90% glia (can’t transmit AP)
Oligodendrocytes- produce myelin, facilitate transmission
Astrocytes- enable homeostasis, physical barrier/connector
Microglia- immune cells of the brain, phagocytose dead cells and debris
10% neurons
All cell types may be affects- damaging in itself, damage neurons
Specific issues in the CNS
In the mature CNS, most neurons are post mitotic (not dividing so can’t be replaced)
Cell death in CNS neurons is more severe than in other tissue
May occur during embryonic development (normal), acute e.g. traumatic event, chronic e.g. disease state
May share common mechanisms of cell death
What is important about a neuron?
Long axon
Metabolic requirements- very energy demanding, cell bodies full of mitochondria, constant use of energy to maintain excitable membrane
Trophic requirements- need energy to move proteins around, growth factors to sustain survival
Types of injury to neurons
Neuronopathy- death of a neuron, loss of all cytoplasmic processes and the myelin sheath, irreversible
Axonopathy- the toxic effect begins in the axon (associated myelin sheath will also degenerate)
Myelinopathy- the myelinating cell or the myelin sheath is the primary target
Axonal transport
Transport intracellular material over considerable distances, energy dependent, disturbance of metabolism/ATP may interfere leading to degeneration of the axon, disturbance of cytoskeleton leads to degeneration of the axon
Degeneration of the axon will occur if it is physically cut
Axonal transport structures
Tubulin exists in alpha and beta heterodimers, polymerise to form micro tubules
MAPs bind to tubulin subunits to regulate their stability/ cross linking
May be stabilizing or destabilizing or guide microtubules
Any disruption in tubulin or MAPs may interfere with axon transport, leading to degeneration
Axonapathies
PNS axons can regenerate, CNS cannot
Peripherally, if toxin removed, Schwann cells distal to the transection divide and act as a guide for axonal sprouts and synthesise nerve growth factor
Axonal transection
Axonal transection (chemical or physical)- accumulation of mitochondira, vesicles, filaments and lysosomes (esp. distal) within axonal swellings on either side of the lesion
Distal portion degenerates, macrophages enter the myelin sheath to take up the axonal debris (more rapid peripherally)
Proximal portion may atrophy as the cell body produces fewer cytoskeletal elements
Myelinopathies
Direct to the myelin or to the myelinating cell
Separation of the myelin lamellae leading to intramyelinic oedema
In the early stages this may be reversible
With severe/prolonged exposure to toxin, segmental demyelination follows
Myelinopathies- macrophages
Derived from microglia, remove most of the degenerate myelin
Astrocytes, oligodendrocytes and Schwann cells may also take up some components
Myelinopathies- remyelination limited in CNS
In the periphery, if the axon is intact it may be complete
The distances between nodes of Ranvier in the remyelinated sections are shorter
Processes involved in cell death
Morphological/physiological characteristics
Biochemical events
Implications of the type of cell death
Apoptosis
Process of a cell suicide under any condition when carried out by a cascade of executioner proteases; a type of programmed cell death- physiological suicide programme critical for the development and maintenance of healthy tissues
Necrosis
Accidental death of a group of cells secondary to traumatic injury
Mechanism of necrosis
Passive disintegration of cell
Dramatic and rapid- every compartment
Environmental insult- excessive injury, normal responses overwhelmed
Neurons have marked dysregulation of ion homeostasis
Breakdown/loss of plasma membrane integrity, swelling, vacuolation of cytoplasm, mitochondrial and ER dilation, gene transcription stops
Take in water and lyse
Contents of cell leaks, lysosomal enzymes escape, inflammatory process to neighbouring cells
Apoptosis mechanism
Active process
Toxic intracellular material packaged into vesicles- phagocytosed by near cells and metabolised
Damaged cells detach and round up
Cell contents packaged into membrane bound apoptotic bodies, engulfed by neighbouring cells
Reduce any inflammatory processes
When do apoptosis and necrosis take place?
Apoptosis: physiological process, development, degenerative diseases
Necrosis: pathological, ischaemia, injury, infection, cancer
Apoptosis death signals
Controlled by a range of cell signals
Intrinsic: response to stress, diverse array of non-receptor mediated stimuli, produce intracellular signals that act directly on targets within the cell, withdrawal of growth factors, hormones and cytokines, DNA damage
Extrinsic: involve transmembrane receptor, mediated interactions
Major players are the caspase enzymes
Family of proteins > 11 cysteine proteases
Inactive until cleaved
Initiator caspases (regulatory)- 2, 8, 9, 10
Effector caspases (disassembly e.g. activated DNAse, endonucleases)- 3, 6, 7
Cleaved in sequence (initiator caspases activate effector caspases)
How are caspases activated? Role of BCL proteins
Bcl-2 (B cell lymphoma 2) family- control integrity and response of mitochondria
Anti and pro apoptotic members:
Anti-apoptotic- Bcl2- stabilises mitochondrial function
Pro-apoptotic- Bad, Bid, Bax and Bak- pore formation in mitochondrial membrane
Other proteins may interact with Bcl2- mitochondrial dysfunction
Activation of caspases by BCL
When cell death triggers occur:
Pro-apoptotic BCL members increase in relation to anti-apoptotic members and oligomerise
Opening of the mitochondrial pore, permeabilising the outer membrane
Permits release of pro-death proteins- cytochrome C from mitochondrial inter membrane space
Apaf-1 in the activation of caspases
Apaf-1 apoptotic protease activating factor exists normally in cytosol as inactive monomer
Interacts with cytochrome C release from mitochondria and caspase 9- forms the apatosome
Transmits apoptotic signals- activate caspase 3 (effector caspase)
Apoptosis growth factor
Growth factors activate PI3K or Akt
These phosphorylate proapoptotic BAD, inhibiting its ability to build up or oligomerise and activate its pro-apoptotic activity
No mitochondrial pore formation
What triggers apoptosis or necrosis in CNS?
Triggers of cell death: withdrawal of growth factors, DNA damage, increased calcium, excitotoxicity, oxidative stress, mitochondrial dysfunction
Each may contribute to apoptosis or necrosis depending on severity and duration of the trigger as well as the type and age of tissue involved
Necrosis- sustained duration triggers- severe intensity
Apoptosis- transient duration triggers- less severe intensity
