PH2113 - Neurodegenerative Disease and Epilepsy 1 Flashcards
What are the cell types of the Central Nervous System?
10% neurones
90% glia
- oligodendrocytes
- produce myelin
- facilitates transmission
- astrocytes
- enable homeostasis
- physical barrier/connector
- microglia
- immune cells of the brain
- phagocytose dead cells and debris
Why might cell death occur in CNS neurones?
During embryonic development
- 50% of neurones formed during development undergo cell death when they fail to make the correct connections
Acutely
- result of traumatic event
- rapid/unexpected cell death
Chronically
- disease state/long duration
- slow
- brain could adapt
- symptoms show when no further adaptation possible
Give examples of causes of cell death in CNS
Environmental toxins
- cigarette smoke
- hydrogen cyanide
- heavy metals
- cadmium
- lead
- mercury
- nerve agents
- ricin
- insecticides
- organophosphates
- alcohol
- adult
- developmental
- foetal alcohol syndrome
Trauma
Disease
- infection
- oxygen deprivation
- viruses
- neurodegenerative diseases
What proportion of cardiac output and oxygen consumption does the CNS need?
15% of cardiac output
20% of total oxygen consumption
Why is there little storage of glycogen in the CNS?
Very little anaerobic respiration takes place
Which structures in the brain are most susceptible to a lack of oxygen?
Hippocampus
Deep cortical layers
Granule and Purkinje cells of the cerebellum
Which structures of the brain are less well vascularised?
White matter is less well vascularised than grey matter
- axon pathways
- less oxygen
What features do neurones have to make them adapted to their function?
Long axon
- high metabolic requirement
- trophic requirements
- take growth factors
Excitable membrane
- high metabolic demand
- maintaining membrane potential
- low Na+ intracellular
- low Cl- intracellular
- high K+ intracellular
- free calcium
What effect does injury have on neurones?
May involve different cell types and different parts of the neurone
- toxic effects may start in the cell body/axon
- toxic effects may start in the myelinating cell
- myelin sheath is the primary target
- myelinopathies
- myelin sheath may degenerate
- Multiple Sclerosis
- neurone function may be altered
- neuronal death
- remyelination very limited in CNS
- oligodendrocytes
- regeneration possible in PNS
- Schwann cells
What is anterograde transport?
Movement down the axon away from soma
What is retrograde transport?
Movement up the axon toward the soma
Why does axonal transport have a high metabolism?
Why does axonal transport have a high metabolism?
Why does axonal transport impair cell survival?
Transport intracellular material over considerable distances
- up to 1 metre
Energy dependent
- loss of mitochondria
Loss of neurotrophic support
Loss of newly synthesised proteins and lipids
Impaired clearance of excess/damaged proteins
- toxic
- build up in synapse
Loss of intracellular signalling
Stress signalling
- information to cell body
What is apoptosis?
Process of cell suicide under any condition when carried out by a cascade of executioner proteases
- controlled
- physiological processes
- development
- degenerative disease
What is necrosis?
Accidental death of a group of cells secondary to traumatic injury or sudden change of environment
- loss of oxygen
- pathological
- ischaemia
- injury
- infection
- cancer
Passive disintegration of cell
Dramatic and rapid
- every compartment of cell disintegrates
Environmental insult
- excessive injury
- normal responses overwhelmed
- ATP depletion
- failure of active transport
- marked dysregulation of ion homeostasis
What are the physical characteristics of necrosis?
Breakdown/loss of plasma membrane integrity
Swelling, vacuolation of cytoplasm
Mitochondrial and endoplasmic reticulum dilation
Gene transcription stops
ATP depleted
Take in water and lyse
- contents of cell leaks
Lysosomal enzymes escape
- normally packaged within lysosomes
Fragments toxic to neighbouring cells
- inflammatory processes
What are the physical characteristics of apoptosis?
Active process
Toxic intracellular material packaged into vesicles
- phagocytosed by near cells and metabolised
- damaged cells detach and round-up
- nuclear contents condense/breakdown
- DNA cleaved into equal sized small pieces
- protrusions from membrane
- blebs
- organelles affected at later stage compared to necrosis
- cell contents packaged into membrane bound apoptotic bodies
- engulfed by neighbouring cells
- recognise phosphatidylserine exposed on cell membrane
What are the three phases of apoptosis?
Initiation
Effector
Degradation
Give examples of death signals that lead to apoptosis
Oxidative stress
Glutamate
Decreased growth-factors
Genetic mutation
How do intrinsic death signals cause apoptosis?
Act directly on targets within the cell
- mitochondrial-initiated events
- withdrawal of growth factors, hormones and cytokines
- loss of apoptotic suppression
- radiation
- toxins
- hypoxia
- hyperthermia
- viral infections
- free radicals
- DNA damage
How do extrinsic death signals cause apoptosis?
Transmembrane receptor-mediated interactions
- TNF receptor gene superfamily
- caspase 8
What are the major players in apoptosis?
Family of proteins
- 11 cysteine proteins
Inactive until cleaved
Initiator caspases
- 2
- 8
- 9
- 10
Effector caspases
- 3
- 6
- 7
Cleaved in sequence
- initiator caspases activate effector caspases
How are caspases activated to kill cells during apoptosis?
Bcl-2 (beta-cell lymphoma 2) family
- control integrity and response of mitochondria
Anti- and pro-apoptotic members
- ratio important
Anti-apoptotic
- Bcl-2
- stabilises mitochondrial function
Pro-apoptotic
- Bad
- Bcl-associated death promotor
- Bid
- Bax
- Bak
- pore formation in mitochondrial membrane
Other proteins like P53, PAR-4 (prostate apoptosis response-4) may interact with Bcl-2 family)
- mitochondrial pore
