PH2113 - Neurodegenerative Disease and Epilepsy 1 Flashcards

1
Q

What are the cell types of the Central Nervous System?

A

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

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2
Q

Why might cell death occur in CNS neurones?

A

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

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3
Q

Give examples of causes of cell death in CNS

A

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

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4
Q

What proportion of cardiac output and oxygen consumption does the CNS need?

A

15% of cardiac output
20% of total oxygen consumption

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5
Q

Why is there little storage of glycogen in the CNS?

A

Very little anaerobic respiration takes place

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6
Q

Which structures in the brain are most susceptible to a lack of oxygen?

A

Hippocampus
Deep cortical layers
Granule and Purkinje cells of the cerebellum

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7
Q

Which structures of the brain are less well vascularised?

A

White matter is less well vascularised than grey matter
- axon pathways
- less oxygen

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8
Q

What features do neurones have to make them adapted to their function?

A

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

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9
Q

What effect does injury have on neurones?

A

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

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10
Q

What is anterograde transport?

A

Movement down the axon away from soma

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11
Q

What is retrograde transport?

A

Movement up the axon toward the soma

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12
Q

Why does axonal transport have a high metabolism?

A

Why does axonal transport have a high metabolism?

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13
Q

Why does axonal transport impair cell survival?

A

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

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14
Q

What is apoptosis?

A

Process of cell suicide under any condition when carried out by a cascade of executioner proteases
- controlled

  • physiological processes
  • development
  • degenerative disease
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15
Q

What is necrosis?

A

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

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16
Q

What are the physical characteristics of necrosis?

A

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

17
Q

What are the physical characteristics of apoptosis?

A

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

18
Q

What are the three phases of apoptosis?

A

Initiation
Effector
Degradation

19
Q

Give examples of death signals that lead to apoptosis

A

Oxidative stress
Glutamate
Decreased growth-factors
Genetic mutation

20
Q

How do intrinsic death signals cause apoptosis?

A

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

21
Q

How do extrinsic death signals cause apoptosis?

A

Transmembrane receptor-mediated interactions
- TNF receptor gene superfamily
- caspase 8

22
Q

What are the major players in apoptosis?

A

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

23
Q

How are caspases activated to kill cells during apoptosis?

A

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