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Pathobiology of Human Disease > Neurological Disease- Intro and Parkinson's > Flashcards

Neurological Disease- Intro and Parkinson's Flashcards

1
Q

What are neurodegenerative diseases?

A

A group of diverse disorders that are characterised by a progressive loss of neurons in specific regions of the CNS

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2
Q

What do clinical symptoms of neurogenerative diseases depend on?

A

Clinical symptoms depend on neurons that are affected
Onset of neurodegeneration usually precedes clinical manifestations by years/decades
Increasing evidence due to aging population

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3
Q

What is the function of neurons?

A

Neurons receive, interpret and transmit information
Carry information
Co-ordinate response

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4
Q

What are the types of neurons?

A

Motor neurons
Sensory neurons

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5
Q

What is the structure of a neurone?

A

Cell body
Nucleus
Axon
Cell membrane
Myelin sheath
Axon terminal

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6
Q

What is the function of the cell body and dendrite in neurons?

A

Cell body- Contains nucleus and other cell organelles
Protein synthesis

Dendrite- Receives stimulus

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7
Q

What is the function of the axon and myelin sheath in neurons?

A

Axon- Transmits stimulus away from cell body to other cells

Myelin sheath- Lipid rich layer surrounding axon, increases speed of impulse conduction

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8
Q

How are electrical signals transmitted?

A

Electrical signals (nerve impulses) are transmitted by chemical messengers (neurotransmitters) to the next cell
Communication of information between cells occurs via a synapse

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9
Q

What do neurotransmitters do?

A

Neurotransmitters transmit chemical messages from one neuron to another across the synapse
Message is communicated from the pre-synaptic cell to a post-synaptic cell

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10
Q

What are some neurotransmitters?

A

Acetylcholine
Dopamine
Noradrenaline
Serotonin (5-HT)
Glutamate
GABA

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11
Q

What is the function of a synapse?

A

To allow communication between neurons or between neurons and another type of cell. It is the critical where information is transmitted within the nervous system

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12
Q

What are glial cells?

A

Provide support for neuron function
Glial cells outnumber neurons
Most abundant cell in the CNS

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13
Q

What are microglia?

A

Resident macrophage in brain
Remove debris (e.g. dead cells)
Defence

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14
Q

What are some examples of glial cells?

A

Microglia
Oligodendrocytes
Astrocytes

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15
Q

What are oligodendrocytes?

A

A type of glial cell
Formation of myelin sheath in CNS

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16
Q

What are astrocytes

A

The dominant glial cell and perform many functions
e.g. they form the blood brain barrier, provide nutrients to neurons and give synapses structural support

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17
Q

What is parkinson’s disease?

A

Progressive neurodegenerative disease
Characterised primarily by abnormalities in movement (motor disorder) and cognitive impairments can also occur
2nd most common neurodegenerative disease
150,000 people in UK have parkinson’s

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18
Q

What is the prevalence of parkinson’s?

A

1% of over 60’s
4% of over 80’s

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19
Q

What are the clinical symptoms of parkinsons?

A

Bradykinesia- slowed movement

Rigidity- Muscle stiffness which limits range of motion

Tremor- uncontrollable shaking

Postural instability- Posture becomes stooped, problems with balance

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20
Q

What are the pathological hallmarks of PD?

A

Profound and selective loss of dopaminergic neurons
Presence of intra-neuronal (cytoplasmic) inclusions of aggregated protein (Lewy bodies)

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21
Q

What causes the loss of dopaminergic neurons in PD?

A

Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)
Dopamine is a neurotransmitter

SNpc controls the initiation and execution of movement
Loss of dopamine neurons causes motor symptoms
Clinical presentation of disease when 50-70% neurons degenerate

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22
Q

What is the unknown hallmark of PD?

A

The molecular basis underlying neuron loss and Lewy body function is not completely understood

23
Q

Is familial PD common?

A

Familial and sporadic forms are often indistinguishable
Gene mutations responsible identified

Familial forms of PD provide an indication of the potential molecular mechanisms underlying disease development
However, familial cases are rare (10%)

24
Q

What are the different hypotheses for PD pathogenesis?

A
  • Protein aggregation (Lewy bodies)
  • Mitochondrial dysfunction
  • Free radical injury (oxidative stress)
25
Q

What is the hypothesis of protein aggregation in PD?

A

Formation of Lewy bodies is a pathological hallmark of PD
Intracellular (cytoplasmic) inclusions formed from the accumulation of aggregated protein
Major constituent is alpha (alpha)-synuclein

26
Q

What is alpha-synuclein?

A

Pre-synaptic, cytoplasmic protein
Role in:
Storage and compartmentalisation of neurotransmitters
Maintaining mitochondrial integrity

27
Q

What does the presence of alpha-synuclein in Lewy bodies?

A

Suggests that this protein is important to PD, protein aggregates thought to acquire toxic properties
Mutations in the alpha-synuclein gene are observed in familial forms of PD
Presence of Lewy bodies (protein aggregates) likely to contribute to neuronal dysfunction and loss

28
Q

What might PD pathogenesis involve dysfunction in?

A

The Ubiquitin-proteasome system (UPS)
The UPS is responsible for the destruction of proteins
Proteins are constantly turning over
Broken down into constituent amino acids and replaced with new proteins

29
Q

What 2 steps do mis-folded and damaged proteins go through in the UPS?

A
  1. Covalent attachment of multiple ubiquitin (protein) molecules to substrate (target protein)
  2. Proteolysis- the ubiquitin-tagged protein is recognized, unfolded, and degraded into peptides by the 26s proteasome, while ubiquitin is recycled
30
Q

What gene is usually seen to be mutated in familial cases of PD?

A

In the gene for parkin protein
Parkin gene encodes a ubiquitin ligase
Catalyses the addition of ubiquitin to proteins (substrate)
Neuroprotective protein

31
Q

What does a mutation in parkin gene lead to?

A

Loss of function mutation in parkin gene leads to an accumulation of neurotoxic parkin substrates in neurons
Could cause cell death
Substrates not identified yet

32
Q

How is PD associated with mitochondrial dysfunction?

A

Mitochondria are abundant in tissues with high energy demands
Mitochondria are a source of ROS in cells
Mitochondrial dysfunction increases ROS production

33
Q

What does the postmortem tissue of substantia nigra in PD patients have?

A

Increased levels of lipid peroxidation, high oxidation of proteins and DNA, lower glutathione (antioxidant) levels

34
Q

What do the levels of oxidation in substantia nigra in PD patients suggest?

A

Suggests that oxidative stress contributes to PD pathogenesis
Mitochondrial dysfunction could promote oxidative stress to cause cell death in PD

35
Q

How is the electron transport chain related to PD patients?

A

Complex 1 is the first enzyme in the system
Dysfunction/inhibition of complex 1 activity in PD patients
Mutations in complex 1 in PD

36
Q

How does dysfunction in complex 1 in ETC affect PD patients?

A

Impairments in complex 1 activity in PD enhances ROS production by mitochondria
Also decreases mitochondrial activity
Less ATP production
Proposed mechanism for dopaminergic neuron death

37
Q

What is MPTP?

A

Abuse of drug MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
This drug causes mitochondrial dysfunction in dopamine neurons
Selective irreversible degeneration of dopaminergic neurons (SNpc)

38
Q

What is MPTP’s mechanism of action?

A

MPTP cross the BBB
Converted to a neurotoxin metabolite (MPP+) by astrocytes
Internalised into the pre-synaptic terminal of dopamine neurons
Transported into mitochondria
Where it inhibits complex 1 of the ECT

39
Q

What other causes are there of inhibition of complex 1 activity?

A

Environmental factors
- Pesticides
- Epidemiology and animal studies identified link

40
Q

What can MPTP be used to generate?

A

PD animal models:
- To test efficacy if therapeutics
- Used to better understand disease pathology

41
Q

What is PINK-1?

A

It is a mitochondrial protein with kinase activity
Helps maintain mitochondrial integrity
Protects from Ox stress
Targets damaged mitochondria for degradation
Neuroprotective properties

42
Q

What does loss of function in PINK-1 cause?

A

Occurs in familial cases of PD
Leads to mitochondria dysfunction
More susceptible to ox stress
Promotes loss of neurons

43
Q

What have animal studies showed in regards to PD?

A

Have shown that exposure to pesticides which impair mitochondrial function can increase risk of PD

44
Q

What other mutation is evident in familial PD?

A

Loss of function DJ-1 mutations
Multi-functional protein
Neuroprotective
Antioxidant

45
Q

What does reduced DJ-1 activity cause?

A

Reduced DJ-1 activity in PD enhances cell death
Leads to ROS generation
Neurons predisposed to oxidative damage

46
Q

What’s important when treating PD?

A

Timing of treatment is likely to impact on success
Ideally, to be effective treatments need to be administered before widespread destruction of nerves

47
Q

Is there a cure for PD?

A

No cure for PD: no treatment to stop or reverse the neurodegenerative process
Patients progressively get worse

48
Q

What can be used to manage symptoms of PD?

A

Pharmaceuticals manage symptoms
Dopaminergic drugs
Treatment is centered on restoring dopamine

49
Q

What is Levodopa (L-Dopa)?

A

Is used as a first line treatment for PD
Precursor to dopamine

Dopamine cannot be given orally as it cannot cross the BBB
Converted to dopamine in the brain by dopa decarboxylase

50
Q

What is L-Dopa often given in combination with?

A

Given in combination with peripheral dopa decarboxylase inhibitor to increase delivery of L-Dopa to the brain and increased duration of action

51
Q

What is MAO?

A

MAO is an enzyme that breaks down neurotransmitters
Inhibitors of MAO activity increase the level of dopamine in the synapse
Selegiline is a MAOI used to treat PD

52
Q

What are dopamine reuptake inhibitors?

A

Inhibit dopamine re-uptake into the pre synaptic nerve terminal
Prolong duration of action of dopamine
Can also stimulate dopamine release from nerves

53
Q

What are dopamine agonists?

A

Dopamine receptor agonsists (e.g. Bromocriptine) are used if L-Dopa is not effective
They bind to dopamine receptors in the brain, stimulating the dopamine system
Lose effectiveness over time
Side effects more serious than L-Dopa

54
Q

How is PD diagnosed?

A

Pathological hallmarks only evident at post mortem
Inherited conditions can be identified
Clinical features and responsiveness to dopamine replacement therapy used for diagnosis

Pathobiology of Human Disease (16 decks)

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