Programmed Cell Death

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Programmed Cell Death
programmed cell death (PCD) is the spatially and
temporally reproducible and species-specific
loss of large numbers of individual cells
during development this does not mean
genetically pre-determined, as most PCD is
caused by environmental cues and cellular
interactions (or lack of them) apoptosis
biochemical suicide of a cell using specific
genes related to PCD, but is more limited than
PCD original idea- nerve cells 'feed' off a
target derived factor for survival
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Programmed Cell Death
PCD seems to involve all neural cells and all
organisms in one form or another, occurring in
both the peripheral and central nervous
system in many cases, up to 1/2 of all neurons
born eventually die before birth in severe
cases essentially ALL of the neurons die it is
not limited to neurons-- oligodendrocyte
precursors also die in both peripheral nerves
and retina by PCD (believed a competition for
axons)
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Programmed Cell Death
2 modes of specifying PCD 1) intrinsic--
assymmetric distribution of cell death
molecules to the somatic cell same way as a cell
differentiates! 2) conditional-- equivalent
cells compete for survival- survival
of the fittest
control extrinsic factor mutant
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Programmed Cell Death
cells dying by apoptosis shrink in size and the
nuclei become very dense (pyknotic), with
cytoplasm pinching off into small blobs or blebs
young brain tissue older brain tissue
necrosis is usually caused by injury or trauma--
initially swelling with membrane rupture and
nuclear condensation later, with
inflammation apoptotic cells are recognized
before rupture necrotic after apoptotic cells
stimulate the immune system far less show DNA
cleavage between nucleosomes giving 180-200bp
DNA fragments
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Mechanisms of Programmed Cell Death
specific genes regulate the processes of PCD and
apoptosis, some overlap neuron survival factors
essentially prevent the activation of PCD
genes PCD requires active RNA transcription and
protein synthesis cell death genes and pathways
are conserved in evolution in all animals with
mitochondria playing a key role 2 possible
reasons why PCD is so common 1) allows
formation of an optimal level of
function-- more adaptive than defined 2)
initial cell divisions may not be accurate
enough to precisely determine the number of cells
required
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Nerve Growth Factor- Prototype Survival Molecule
originally identified in the 1950's (ie. around
time DNA double helix) neurotrophic factors
were identified by their ability to allow neurons
to surivive in culture or to send out more
axons in vivo, NGF allowed more target neurons
to survive blocking kills cells NGF
co-receptors trkA p75 required at target, not
soma retrogradely transported
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Neurotropin Family of Molecules
BDNF (brain derived neurotropic factor) was
purified from pig brains NT-3, NT-4/5, NT-6 were
cloned using PCR all have a similar 3D structure
and sequence homology of about 50 a 250 aa
precursor is processed into a 120aa functional
molecule exists as a disulfide-bonded dimer
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Neurotropin Receptors
p75- abundant NGF receptor, but low affinity by
itself and its mechanisms remain
unclear-- may bind to all NTFs trkA- low
abundance, but very high affinity for NGF trkB-
binds BDNF and NT-4/5 trkC- binds NT-3 all trks
have a common structure 3 leucine rich motifs
2 cysteine clusters 2 Ig fold domains
intracellular tyrosine kinase alternative
splicing makes kinase-inactive isoforms,
potentially binding NTFs but not allowing
normal signaling
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Neurotropin Secretion and Processing
both processed and partially processed NTFs
confer biological signaling p75 seems to prefer
unprocessed proteins combinations of binding
proteins and NTF processing determines function
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Neurotrophins and Synaptic Function
neurotropins are released constituitively and in
activity-dependent fashion high frequency bursts
release using activity also depends upon cAMP
signaling pathway a natural BDNF mutation
causes learning and memory defects in humans
weak linkage to schizophrenia seems to affect
activity dependent release at synapses
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Neurotrophins and Synaptic Function
retrograde axonal signaling uses endocytosis of
trkA receptors transported back to the cell
body using microtubules trkA binds directly to
dynein light chain activated trkA then changes
gene expression via phosphorylation receptors
then can be recycled back to the axonal arbor
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Neurotropin Signaling Pathways
trkA functions as a normal tyrosine kinase-
receptor dimerization phosphorylation AKT
phosphorylate CREB, the cAMP response element
binding protein to regulate transcription also
inhibits caspase-9 and BAD apoptotic
activators
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Cytokines Have Multiple Effects
cytokines are growth/survival factors for various
tissues many cytokines have effects in the
nervous system epidermal growth factor (EGF) and
fibroblast growth factor-2 (FGF-2) work
together to support neural stem cell survival and
replication cytokine response differs by tissue
and developmental stage in the CNS,
cytokines/neurotrophins probably have overlapping
function
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Target Dependent Cell Death
signals blocking cell death can be neuronal and
non-neuronal best studied neural cases have
neurons forming synapses on target
cells reducing target populations increases
cell death increasing target populations
decreases cell death surviving avian motor
neuron number determined by myotubes during
the period of cell death, NOT the final
number present in the muscle neurons losing the
competition die
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Target Dependent Cell Death
activity is also required for neuron cell death
by competition blockading all activity prevents
cell death delaying activity delays
choice pruning of dendritic arbors and
synaptic arbors take place
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Cell Death and Neuropathology
Parkinson's- loss of dopamine neurons in the
substantia nigra Alzheimer's- loss of
cholinergic neurons in the forebrain multiple
sclerosis- loss of oligodendrocytes producing
myelin
control Alzheimer's
some losses genetic- some environmental