Neuro 210

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Neuro 210
2010-04-12 12:57:32
cell death in the cns lecture

cell death in the cns lecture
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  1. Different causes of cell death in the CNS
    • Developmental--important, need some cells to die off if you have too many
    • Trauma
    • Toxins like alcohol (shrinks brain, causes atrophy), pesticides, heavy metals
    • Cerebrovascular disease like stroke
    • Infectious agents like HIV, meningitis
    • Genetic diseases like Huntingtons
    • Tumors
    • CJD--mad cow, brain becomes spongy
    • Parkinsons--substantia nigra dies
    • multi-infarct dementia--tiny strokes that lead to dementia
  2. What happens at a cellular level?
    • Neurons and glia
    • - neurons more vulnerable, live on the edge of death because they dont have the capacity to store energy
    • - brain consumes 25%-50% of oxygen and glucose in the bloodstream
    • - neurons use glucose as their primary carbon source
    • - neurons are not replaced in significant numbers, once lost there is no good replacement strategy
    • - glia are the reactors to injury, involved in killing of injured neurons
  3. Appropriate cell death (clean cell death)
    Developmental die-off --produce more neurons than we need, form functional connections between parts, and then get rid of cells not involved in connections

    • – During development more neurons that will be needed are born
    • – Fine tuning of connections orchestrated by interactions with the environment (macro and microenvironments)
    • – Developmental cell death occurs without tissue inflammation or disruption of surrounding cells
    • – ‘Use it or lose it’ principle that involves growth factors and electrophysiological activity
    • – This type of cell death is programmed by the DNA for establishment of the central nervous system and is therefore considered ‘appropriate’.
  4. Homeostasis
    - Normal cell is in a steady state, injury is any stimulus bringing changes in cell physiology and or anatomy, internal or external

    - three parts of injurious phase: adaptation, reversible, irreversible---> (cell death)

    • - Injury can be reversible/irreversible
    • - Adaptation results from the changes in a cell due to reversible injury
    • - irreversible damage leads to cell death
  5. routes to cell death--glutamate induced death
    • Glutamate-induced neuronal death
    • - initially there is an energy failure, disturbance causing lack of oxygen or glucose to cell
    • – excitotoxicity (too much glutamate)
    • – excessive stimulation through receptors for neurotransmitter glutamate (most widely used excitatory transmitter)
    • – caused by excessive release, failure of glutamate uptake mechanisms, exposure to drugs or poisons
    • that act just like glutamate (agonist)
    • – too much glutamate activity causes an imbalance of other ions such as calcium and sodium which can result in cell death--causes intracellular events that lead to programmed or necrotic cell death
  6. Routes to cell death--reactive oxygen species
    • - Molecules with a free electron that can bind with other things (free radicals)
    • – will damage cell membranes and intracellular organelles
    • – will activate programmed cell death mechanisms
  7. Route to cell death: hypoglycemia
    • – loss of glucose leads to rapid depletion of cellular energy reserves
    • – will activate programmed cell death mechanisms
  8. Inappropriate cell death
    • Neurons do not all die in the same fashion or for the same reasons:
    • two kinds of cell death:
    • - necrosis--rapid, messy death
    • - apoptosis--programmed cellular suicide
  9. Necrosis
    dramatic and rapid cell death in which every compartment of the cell disintegrates, doesn't have the energy/means to keep it all together

    • characterized by marked dysregulation of ion homeostatis causeing:
    • - swilling
    • - dialation of mitochondria and ER
    • - formation of vacuoles in cytoplacm
    • - activation of enzymes called proteases which degrade cellular components (normally held in lysosomes but released through necrosis)

    • process
    • - chromatin clumps and nuclear membrane ruptures and leaks
    • - gene transcription and protein synthesis stops (because of no energy)
    • - ATP is depleted
    • - Cells lyse and spill contents into ECF
    • - contents can damage neighbouring cells, spreading damage
    • - inflammatory response occurs.
  10. Continuum
    very few processes that only induce necrosis or apoptosis

    • whether a cell undergoes apoptosis or necros
    • is is determined primarily by the intensity of duration of the
    • death inducing stimulus
    • - if stimulus is sever and sustained like glutamate excitotoxicity, trauma, energy failure--necrosis
    • - if stimulus is less severe with transient stresses it will induce apoptosis
  11. Apoptosis
    - can be appropriate or inappropriate depending on what is the cause

    • two main pathways:
    • - intrinsic--generated by signals arising within the cell--e.g. needed to separate fingers, make nostrils open, open mouth
    • - extrinsic--triggered by death activators bidning to receptors at the cell surface

    also: caspase independent pathway.
  12. Intrinsic pathway
    aka mitochondrial pathway

    • • Pathway is largely conserved from worms to mammals
    • • Involves the interplay of a family of proteins. Some members of this family will act to prevent apoptosis (antiapoptotis) and some will act to promote apoptosis (pro-apoptotic). This
    • family is referred to as the Bcl-2 family (B cell leukemia/lymphoma 2)
    • • Once the interplay within Bcl-2 family members is complete and if the pro-apoptotic members won, the program continues through the activation of the program executors – the caspases (cytosine-dependent, aspartate-specfific proteases)
  13. Intrinsic--what happens if the pros win
    • The pro-apoptotic winner causes a pore to open in the mitochondria
    • • Out of the pore leaks cytochrome C (amoungst other compounds)
    • • Cytochrome C binds with a molecule called apoptosis activating factor-1 (APAF-1) and induces it to create the first stage of an apoptosome.
    • • Together APAF-1 and cytochrome C capture and bind caspase-9 which completes the apoptosome
    • • If nothing stops the program at this stage, the apoptosome will progress to the next step – activation of the final apoptosis executor – caspase-3
  14. Extrinsic pathway
    Starts with something in blood stream and binds to cell and causes internal events to occur. Ligand binds to outer portion of receptor, changes the way it looks and exposes death domain.

    • The death receptors (Fas, TNF, DRs) are proteins embedded through the cell membrane with their receptor domains exposed at the cell surface
    • • Best characterized is Fas receptor.
    • – Fas ligand (FasL) binds at this receptor
    • – This binding causes activation of the receptor and its death domains
    • • Once the death domain is activated, it recruits/captures caspase-8
    • • The binding of the death domain and caspase-8 causes activation of the caspase-8.
    • • Activated caspase-8 then proceeds with the death plan by activating the final death effector caspase-3
    • • The extrinsic pathway does have a mechanism to interact with the intrinsic pathway that involves caspase-8.
    • – Caspase-8 can activate a pro-apoptotic molecule typically associated with the intrinsic apoptotic pathway thus the 2 pathways can work towards death simultaneously
  15. Communication between extrinsic and intrinsic
    Caspase 8 can initiate intrinsic pathway as well as being involved in extrinsic

    brain tries to release proteins to stop the process such as Diablo, Omi/HtrA2, XIAP
  16. Caspase Independent pathways
    • Looks like intrinsic but what leaks out of the mitochondria is AIF, caspase not needed
    • Activated when an intense signal is delivered

    • - Through apoptosis inducing factor (AIF)
    • - Normally located in intermembrane space of mitochondrion
    • - When cell received signal to die:
    • AIF released from mitochondira
    • migrates to cell nucleus
    • binds to DNA
    • triggers destruction of DNA and cell death
  17. Apoptosis vs Necrosis
    • Two processes are temporally dislocated and likely represent two extremes of a continuum
    • – Necrosis process can start only and exclusively when the cell dies and is an irreversible process – no return
    • – Secondary necrosis--when a cell has progressed to such a point that it will die

    see lecture notes for comparisons