Neuronal Cell Death I Flashcards
7 triggers of neuronal loss
proteosome dysfunction
inflammation
excitotoxicity
oxidative stress
AB tangles
trophic factor withdrawal
reduced energy availability
misfolded/aggregated proteins in neurodegenerative conditions
a-synuclein in lewy bodies in PD
tau aggregates in FTD
huntingtin - HD
Amyloid Beta - AD
protease dysfunction steps (ubiquitination)
1) activation of ubiquitin-activating enzyme E1 by addition of ubiquitin molecule
2) transfer of ubiquitin molecule to cysteine residue in ubiquitin-conjugating enzyme (E2)
3) formation of peptide bond between ubiquitin bound to E2 and lysine residue in target protein catalysed by ubiquitin ligase E3
4) heavy ubiqutinated protein recognised by proteaosome barrel which cleaves ubiquitin tagged proteins to yield short peptides and intact ubiquitin
autophagy
highly conserved lysosomal process for energy provision during nutrient deprivation
removes damaged organelles
failure leads to protein accumulation
cause of ER stress
accumulation of unfolded proteins/calcium overload
UPR = unfolded protein response causes cell death
ER tells machinery to stop making protein (stop translation) nucleus makes more folded proteins
excitotoxicity
an overexcitation of neurons involving: glutamate, Ca2+ dependent mechanisms, free radicals (oxidative stress)
glutamate paradox
L-glutamate is the excitatory NT
involved in learning/memory/synaptic plasticity/survival signalling
neurotoxic
disorders associated with glutamate excitotoxicity
head trauma
stroke
AD
PD
HD
MND (ALS)
epilepsy
cognitive decline
what mediates glutamate excitotoxocity
mostly NMDA R
AMPA R (in ALS)
evidence of excitotoxicity
high glutamate doses cause retinal neuron degeneration
glutamate/glutamate analogues (NMDA) injection cause cell loss at postsynaptic dendrites/soma
prolonged stimulation of perforant pathway causes seizures
high dose of glutamate/NMDA/kainate kills neurons
cell death prevented by glu R ant (protection against cerebral ischaemia)
dietary excitotoxins
domoate (Kainate R) - seaweed - limbic seixures and amnesia
BOAA (AMPA agonist) - chickpeas - neurolathyrism/spastic paraplegia
BMAA (AMPA/NMDA agonist) - guam disease/ALS/dementia/muscle wasting/parkisonism
mechanisms of ca2+dependent neuronal loss
apoptosis/caspases
stress activated protein kinases (SAPKs)
phospholipase A2
mitochondrial dysfunction
NO synthase
calpains/proteases
endonucleases (errors in transcription)
role of PLA2 in excitotoxicity
mobilies arachidonic acid - blocks glutamate transporters (glt-1) prevents glutamate uptake into glia
what is arachidonic acid a precursor of
cycloxygenase - prostoglandins (PG)/thromboxanes (TXA)
epoxygenase - epoxides
lipoxygenase - leukotrienes/HETE’s
elevates following ischaemia/induction of COX-2
NO signalling
causes sustained release of glutamate
1) produced in neurons following Ca2+/CaM activation of nNOS
2) produced in microglia by inducible NOS during inflammation
3) NO combines with superoxide to form damaging intermediate peroxynitrite
