Lecture 5 - Neuronal Death and Neurodegeneration Flashcards
What are some pathological differences in APOPTOSIS vs NECROSIS?
Apoptosis
- Individual single cells
- Cell shrinkage
- Membrane preservation, cell surface blebbing
- Involution, contraction, ‘apoptotic bodies’
- Chromatin condensation and fragmentation
- Internucleosomal DNA fragmentation, free 3’ ends
- Phagocytosis without cell filtration/inflammation
Necrosis
- Whole group of cells
- Cell swelling and lysis
- Early membrane breakdown
- Organelle swelling and disruption
- Karyolysis, pyknosis (or karyorrhexis)
- Diffuse and random DNA degradation
- Marked inflammation, macrophage invasion
What is the General structural feature of caspases?
C (cysteine pmtease) aspase (cleave after aspartic acid (asp)
Active caspase 3 - tetramer made up of two p17 and two P12 subunits (prodomain cleaved)
The mitochondria is a central control point of apoptosis
Which factors do mitochondria release that lead to apoptosis?
- Cytocrome c
apoptosome activation, intrinsic pathway - Smac/Diablo
interact with inhibitors of apoptosis (IAPs), thus
relieving their inhibitory effects on caspases - Apoptosis inducing factor (AIF)
regulate mitochondrial permeability, translocates into nucleus and causes DNA fragmentation - Endonuclease G
translocates into nucleus and causes DNA fragmentation
Caspase-independent programmed cell death
How do autophagy pathways of “necrotic” death involve calpain and cathepsin?
Upon induction of necrotic insults, intracellular Ca2+ is increased mainly by release from ER, which activates mu-calpain. Parallel to activated calpain-induced Iysosomal rupture, autophagy is upregulated directly and/or through calpain activation, but eventually synergizes with extra-lysosomal cathepsins to mediate cell death.
Why and when would neurons die?
During development - Lack of target innervations and survival signal input
Trauma and injury - Primary physical injury or secondary insults
Neurodegenerative diseases - Oxidative stress, metabolic disorders, toxic substances
How does neuronal apoptosis occur during development?
Neurotrophins bind to a family of receptor tyrosine kinases known as Trks and are essential for neuronal survival
Different classes of neurons in the dorsal root ganglia (DRG) require different trophic factors for survival
Deprivation of neurotrophic factors activates apoptosis in sympathetic neurons
(Neuronal survival pathways induced by the binding of NGF to its receptor)
Neuronal death caused by vascular damage and physical injury
How does cerebral ischemia/stroke result in a catastrophic cascade of events leading to massive neuronal cell death?
Molecular mechanisms of injury and death during cerebral ischemia and reperfusion
- Acute excitotoxic death: Generation of free radicals, lipolysis and lipid peroxidation
- Acute excitotoxic death: Initiation of programmed cell death
- Delayed death: Inflammation
Neuronal death during ischemia is a complex process involving multiple modes of cell death
How does it occur?
Molecular cross-talks between apoptosis (caspase) and necrosis (cathepsin) cascades occur during ischemia.
Ca2+-mobilization during the ischemic insult activates g-calpain at the lysosomal membrane of CA1 neurons to induce release of cathepsins B, L and D that leads to necrosis.
Alternatively, cathepsin B triggers activation of caspase 11 and subsequently caspase 3, which leads to apoptosis.
Further, the interaction of cytosolic cathepsins with BcI-2 family members has the potential to induce mitochondrial apoptosis.
Extents of Ca2+-mobilization and lysosomal destabilization may influence cell death pattern.
Neuronal cell death in neurodegenerative diseases
A variety of neurodegenerative diseases stems from loss of specific cells different parts of the nervous system
Which brain regions are typified by selective apoptosis of neurons in Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease?
In Alzheimer’s disease, neurons in the hippocampus and certain regions of the cerebral cortex degenerate.
In Huntington’s disease, neurons in the striatum die.
In Parkinson’s disease, dopaminergic neurons in the substantia nigra (not shown here) undergo apoptosis
In stroke, the neurons that die are those supplied by an occluded or ruptured blood vessel.
Alzheimer’s disease (AD) is strongly correlated with synaptic degeneration and death of neurons in limbic structures, the hippocampus, amygdala and associated regions of the cerebral cortex
What are the Major pathological features?
Aß-deposits in senile plaques and Neurofibriliary tangles
What are the molecules implicated in the pathogenesis of Alzheimer’s disease?
Amyloid-β protein
Tau
Presenilins
Apolipoprotein E
What are the mechanisms underlying the pro-apoptotic actions of altered APP processing and presenilin-1 mutations
Proteolytic processing of Amyloid precursor protein (APP):
- Aß production by ß— and y-secretase. Aß can self-aggregate under certain conditions and induce membrane lipid peroxidation which can impair the function of ion pumps and glucose transporters. Neurons are thus sensitize to death by apoptosis
Mutations in presenilins in Familial Alzheimer’s:
- presenilins are multiple membrane spanning proteins that are important for the processing of several proteins, including APP and Notch.
- mutant presenilins increase the production of Ab
- mutant presenilins increase susceptibility to apoptosis
How does APP processing and Aβ generation occur?
Cleavage by BACE - soluble APP beta
Gamma-secretase - release a-beta, intramembranous cleavage
If alpha-secretase cleaves APP first, there will be no a-beta
How is amyloid-beta protein is neurotoxic in vitro and in vivo?
The Amyloid Cascade Hypothesis:
Neurodegeneration in AD is cause by deposition of Aß as amyloid plaques in brain tissue
Aß cause apoptosis directly in cultured neurons (apparent through a p53 and Bax-dependent pathway)
APP is a substrate for caspase-3. Caspase 3 cleavage of APP can release a C-terminal peptide with potent apoptosis inducing property
In neurons associated with amyloid deposits:
- Increase DNA damage
- Increase caspase activity
- Alterations in expression of apoptosis-related genes
The mechanism by which Aß sensitizes neurons to cell death involves membrane lipid peroxidation and mitochondria associated mechanisms
Parkinson’s disease is associated with increase oxidative stress and mitochondria dysfunction in dopaminergic neurons
What is it characterised by?
PD — selective and progressive loss of dopaminergic neurons of the substantia nigra
Pathological features include a-synuclein-rich Lewy Bodies.
Mostly idiopathic. Genetic: a-synuclein, parkin, DJ-I, LRRK2 mutations.
Some evidence of apoptotic cell death by apoptosis in postmortem Parkinsonian brain
normal
