Animal Models of Parkinson's Disease Flashcards

1
Q

State the primary quartet of symptoms in PD

A

Bradykinesia, resting tremor, rigidity, loss of postural reflexes

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2
Q

State some symptoms of autonomic dysfunction

A

Constipation, postural hypotension, urinary frequency and urgency, impotence, increased sweating

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3
Q

State some symptoms of PD other than the primary quartet

A

Depression, pain, taste disturbances, anosmia, cognitive decline and dementia, hallucinations, anxiety, confusion, sleep disturbances, autonomic dysfunction

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4
Q

Do animals naturally develop PD?

A

No

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5
Q

How many more nigrostriatal connections are there in the human brain than the mouse brain?

A

150,000

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6
Q

Why might human nigrostriatal connections be more vulnerable than mouse migrostriatal connections?

A

Many more connections, greater ATP requirement, more mitochondrial activity, more alpha-synuclein mediated neurotransmission

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7
Q

Name the 2 main types of animal model

A

Toxin-treated, genetically-altered

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8
Q

Name 3 toxin-treated animal models of PD

A

6-hydroxydopamine (6-OHDA), MPTP, lactacysteine

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9
Q

Summarise the features of the 6-hydroxydopamine model

A

Mitochondrial inhibition, selective neuronal loss, iron accumulation causing oxidative stress. No altered proteins

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10
Q

Summarise the features of the MPTP model

A

Mitochondrial inhibition, selective neuronal loss, iron accumulation causing oxidative stress. May cause altered protein formation and deposition if co-administered with probenecid

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11
Q

Summarise the features of the lactacystin model

A

Selective neuronal loss, iron accumulation causing oxidative stress, altered protein formation and deposition

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12
Q

Name 4 toxins known to cause parkinsonism in humans

A

MPTP, manganese, carbon disulphide, cycad seeds

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13
Q

Describe the features of manganese-induced parkinsonism

A

Fixed gaze, bradykinesia, postural difficulties, rigidity, dystonia

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14
Q

Describe how 6-OHDA is administered to rodent models

A

Stereotactic injection into the medial forebrain (loss of cells over 7-9 days) or striatum (slower loss) unilaterally into anaesthetised animals

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15
Q

Why is 6-OHDA not used to create a bilateral lesion?

A

Bilaterally lesioned animals have difficulty eating

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16
Q

Why is 6-OHDA not injected directly into the substantia nigra?

A

The dopaminergic neuron loss occurs too rapidly to adequately mimic PD

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17
Q

State the 4 ways in which animal models must be valid

A

Construct validity, face validity, aetiological validity, predictive validity

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18
Q

What is 6-OHDA?

A

An unstable oxidative by-product of dopamine

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19
Q

Name a way of assessing motor asymmetry in the 6-OHDA rodent model

A

Amphetamine-induced rotational assessment

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20
Q

Name 2 animals which MPTP can be used in

A

Non-human primates, C57black mouse

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21
Q

How does MPTP cause parkinsonism?

A

It inhibits complex I and causes oxidative stress, resulting in mitochondrial inhibition

22
Q

Name the compound co-administered with MPTP to cause protein inclusion formation and state why it is required

A

Probenecid, to prevent clearance of the active molecule MPP+

23
Q

Why are dopaminergic neurons particularly susceptible to MPP+?

A

They have high energy requirements due to being long and poorly myelinated, and they contain neuromelanin which accumulates MPP+

24
Q

Describe the effect of MPTP on non-human primates

A

After 3 doses, they develop a persistent parkinsonian behavioural syndrome which an akinetic, flexed posture, increased limb rigidity, tremor, clumsiness, and freezing episodes

25
Q

Why does MPTP not affect most animals?

A

It and its active form MPP+ are rapidly removed from the brain - it only persists if there are high levels of neuromelanin

26
Q

State the pathological correlate of MPTP-induced parkinsonian behaviour

A

Persistent and severe depletion of dopamine in the caudate and putamen due to dopaminergic cell loss in the substantia nigra. The adjacent ventral tegmental area is not affected

27
Q

Can MPTP-induced behavioural changes be reversed?

A

Yes, with L-DOPA or dopamine agonists

28
Q

What are proteasomes?

A

Part of the cellular machinery that degrades altered proteins

29
Q

Why is the proteasome inhibitor PSI no longer used?

A

It did not produce reproducible results

30
Q

Name a proteasome inhibitor model

A

Lactacysteine

31
Q

Describe how lacatcystin is administered and its effects

A

A single admission by stereotactic surgery to the substantia nigra produces microglial activation, nigral cell loss, protein inclusions, and chronic progression

32
Q

Name the 3 PD-causing gene mutations identified in alpha-synuclein

A

A53T, A30P, E46K

33
Q

What is the most commonly affected gene in familail PD?

A

LRRK2

34
Q

Describe a Drosophila model of PD

A

Drosophilae flies overexpressing alpha-synuclein develop selective neuronal cell death, dense, Lewy body-like structures, and a reduction in climbing ability during flight

35
Q

Describe the effect of wild-type alpha-synuclein overexpression on mice

A

These transgenic mice develop non-fibrillar neuronal inclusions, but without any cell loss or other neuropathological features of PD

36
Q

Do mice expressing a single alpha-synuclein gene mutation have any pathological features?

A

No

37
Q

Describe a transgenic mouse model of PD

A

Transgenic mice expressing the A30P/A53T double mutant form of alpha-synuclein show an age-dependent decline in substantia nigra cell number and a reduction in motor function, but no protein inclusions

38
Q

State 2 disadvantages of the transgenic mouse model of PD

A

1) Expensive to produce
2) Must be maintained for a long time to see age-related neurodegeneration
3) No human with PD has ever had an alpha-synuclein double mutation

39
Q

Describe a more effective way of genetically altering mice to express parkinsonism than transgenics

A

Transfection with a viral vector

40
Q

Describe a viral transfection mouse model of PD

A

The rAAV-alpha-synuclein model produces a loss of dopaminergic striatal terminals and cell bodies with progressive motor behaviour deficits

41
Q

Describe the effect of injecting pre-formed alpha-synuclein fibrils into the mouse striatum

A

The fibrils are taken up by neurons and result in the formation of inclusions resembling Lewy bodies and neurites. The fibrils cause native alpha-synuclein to misfold, with inclusions spreading throughout the brain. However, this model produces little dopaminergic neuron loss and no behavioural deficits

42
Q

Describe the effect of LRRK2 mutations in vitro

A

They produce apoptotic cell death in neuroblastoma cells and mouse cortical neurons

43
Q

Describe the effect of LRRK2 mutations on mice

A

Synaptic dopamine dysfunction occurs with some movement dysfunction, but no neuronal loss

44
Q

What is the MitoPark mouse?

A

A Tfam knockout mouse with reduced mitochondrial DNA expression and mitochondrial respiratory chain deficiency in dopaminergic neurons, leading to adult-onset striatal neuronal loss with inclusions and progressive motor impairment

45
Q

Describe the theory behind the MitoPark mouse

A

Tfam - mitochondrial transcription factor A - directly regulates mitochondrial DNA transcription, which encodes 12 respiratory chain subunits. Mitochondrial DNA mutations increase with age, and PD patients have more mitochondrial DNA mutations in dopaminergic neurons than age-matched controls

46
Q

Name 2 drugs which entered human clinical trials for PD based on mouse models

A

Deferiprone (iron chelator) and pioglitzaone (anti-inflammatory and blood glucose regulator)

47
Q

Describe the results of human clinical trials for deferiprone for PD

A

It decreased the level of iron in the brains of PD patients with a corresponding improvement in motor symptoms

48
Q

State a disadvantage of deferiprone

A

It causes neutropenia in 1% of patients, which can progress to agranulocytosis, so necessitates weekly haematological monitoring

49
Q

Describe the result of human clinical trials of pioglitazone for PD

A

It failed at phase II - but epidemiological studies indicate that glitazone-treated individuals have a 28% lower incidence of PD, so it is possible that it is neuroprotective but once symptom-onset has started it is too late for it to be beneficial

50
Q

State at least 4 obstacles to neuroprotection

A

Incomplete understanding of disease pathogenesis, lack of accurate animal models, challenges in clinical trials, need for validated biomarkers, insensitive end-points and outcome measures, may be applying treatments too late