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Molecule to Malady > Lecture 22 - Parkinson's Disease > Flashcards

Lecture 22 - Parkinson's Disease Flashcards

1
Q 
Motor symptoms of PD
1)
2)
3)
4)
5)
6)
7) 
8)
A

1) Slowness
2) Stiffness
3) Tremor
4) Postural instability
5) Stooped, shuffling gait
6) Decreased arm swing when walking
7) Difficulty swallowing
8) Immobile facial expressions

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2
Q 
Cognitive symptoms of PD
1)
2)
3)
4)
5)
6)
A

1) Mood changes
2) Depression
3) Anxiety
4) Pain
5) Tiredness
6) Confusion

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3
Q 
Sensory symptoms of PD
1)
2)
3)
4)
5)
A

1) Numbness
2) Aching
3) Restlessness
4) Pain
5) Anosmia (loss of sense of smell)

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4
Q

Autonomic symptoms of PD
1)
2)

A

1) Hot/cold sensations

2) Constipation

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5
Q

Characteristic anatomical feature of PD

A

Severe loss of substantia nigra dopaminergic neurons (with reduced pigmentation)

60-70% loss of substantia nigra neurons when symptoms present

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6
Q

Functions of substantia nigra
1)
2)

A

1) Controls voluntary movement

2) Produces neurotransmitter dopamine, which regulates mood

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7
Q

Where is the substantia nigra located?

A

Located in the midbrain

Part of the basal ganglia

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8
Q

What are the basal ganglia?

A

Clusters of neurons located in the white matter of the cortex

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9
Q 
Components of the basal ganglia
1)
2)
3)
4)
A

1) Striatum (putamen, caudate)
2) Globus pallidus
3) Substantia nigra
4) Subthalamic nuclei

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10
Q

Two parts of the substantia nigra

A

1) Pars compacta

2) Pars reticulata

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11
Q

Pars compacta features

A

Large, pigmented neurons with neuromelanin

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12
Q

Pars reticulata features

A

Unpigmented neurons

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13
Q

What does the pars compacta primarily project to?

A

The striatum (caudate and putamen)

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14
Q

Role of striatum

A

Major role in planning and modulation of movement pathways

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15
Q

Area of substantia nigra most affected by PD

A

Most neuronal loss in venterolateral area of substantia nigra (this part projects to the striatum)

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16
Q

Name of pathway between substantia nigra and striatum

A

Nigrostriatal pathway

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17
Q

Suggested mediators of idiopathic PD
1)
2)
3)

A

1) Toxins (EG: pesticides)
2) Metals
3) Drug MPTP (byproduct of synthetic opiate MPPP)

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18
Q 
Genes involved in familial PD
1)
2)
3)
4)
5)
A

1) Alpha-synuclein
2) Parkin
3) Leucine-rich repeat kinase (LRRK2
4) DJ-1
5) PINK1

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19
Q

Prevalence of Lewy pathology in non-symptomatic individuals over 60

A

5-20% of non-PD people over 60 have Lewy bodies

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20
Q 
Alpha-synuclein protein structure 
1)
2)
3)
4)
A

1) 140aa in length
2) Three regions:
a) 7xKTKEGV
b) Non-Abeta component
c) Acidic domain
3) Natively unfolded
4) Can anchor in membranes

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21
Q

7xKTKEGV
1)
2)
3)

A

1) Region of alpha-synuclein
2) Rich in basic amino acids
3) High tendency for alpha helical formation

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22
Q

Non-Abeta component
1)
2)
3)

A

1) Also present in Abeta
2) Hydrophobic region
3) Region in alpha-synuclein

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23
Q

Acidic domain
1)
2)

A

1) Region in alpha-synuclein

2) Mainly negatively charged

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24
Q

Possible role of alpha-synuclein

A

Learning, development, synaptic plasticity associated with vesicles
Possible regulator of vesicle transport, dopamine release

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25
Q

Name for stages of PD based on Lewy body location

A

Braak staging

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26
Q

Stage 1 of Braak

A

Lewy bodies in dorsal motor nucleus of vagus nerve, anterior olfactory structures

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27
Q

Stage 2 of Braak

A

Lewy bodies in lower raphae nuclei, locus coeruleus

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28
Q

Locus coeruleus

A

Located in brainstem, controls responses to stress, panic

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29
Q

Stage 3 of Braak

A

Lewy bodies in substantia nigra, amygdala, nucleus basilis of Meynert

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30
Q

Stage 4 of Braak

A

Lewy bodies in temporal mesocortex

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31
Q

Stage 5 of Braak

A

Lewy bodies in temporal neocortex

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32
Q

Stage 6 of Braak

A

Lewy bodies in neocortex, primary sensory and motor areas

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33
Q

When in Braak stages do symptoms normally present?

A

Stage 3

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34
Q

Common way to detect alpha-synuclein amyloid deposits

A

Relative thioflavin T fluorescence

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35
Q

Factors modulating alpha-synuclein aggregation
1)
2)
3)

A

1) Genetics (mutations in alpha-synuclein)
2) Dopamine (inhibits aggregation)
3) Exposure to factors that promote aggregation (iron, oxidants, nitration, exposure to environmental toxins)

36
Q

Effect of metal presence on alpha synuclein aggregation

A

Increases aggregation

EG: FeCl3, etc

37
Q

Effect of dopamine on alpha-synuclein oligomers

A

Alpha-synuclein monomers take ‘off’ pathway, forming non-thioflavin T reactive oligomers

38
Q

How are mutations in alpha-synuclein inherited?

A

Autosomal dominant

39
Q

Types of alpha-synuclein mutations
1)
2)

A

1) Malformed protein

2) Duplication of gene (leads to increased gene product)

40
Q

Effect of A53T mutation

A

Alpha-synuclein mutation
Shorter lag phase in amyloidogenesis
Greater relative thioflavin T fluorescence by end of experiment

41
Q

Effect of A30P mutation

A

Alpha-synuclein mutation
Shorter lag phase in amyloidogenesis
Same relative thioflavin T fluorescence by end of experiment as wild type

42
Q

Effect of higher alpha-synuclein concentration

A

Increases aggregaiton

43
Q

Phenotype of transgenic mice expressing A53T mutation

A

Motor deficit, Lewy body pathology

100% disease by 16 weeks

44
Q

Phenotype of transgenic mice overexpressing human alpha-synuclein gene

A

Movement disorder

45
Q

Promotor in alpha-synuclein gene in transgenic mice

A

Human platelet-derived growth-factor beta

46
Q

Tyrosine hydroxylase

A

Enzyme involved in dopamine formation

47
Q

Effect of alpha-synuclein overexpression on tyrosine hydroxylase

A

Tyrosine hydroxylase levels decrease, activity decreaess

48
Q 
How was propagation of alpha-synuclein demonstrated?
1)
2)
3)
4)
A

1) Inject brain homogenate from symptomatic M83 mice into brain of asymptomatic M83 mice
2) Alpha-synuclien deposits formed in parts of the brain other than where brain lysate was injected
AND
3) Inject recombinant, myc-tagged alpha-synuclein preformed fibrils into brain of asymptomatic M83 mouse
4) Same results as 1) and 2)

49
Q

M83 mice

A

Transgenic mice overexpressing A53T alpha-synuclein gene

50
Q

Neuronal release of alpha-synuclein
1)
2)
3)

A

1) Secretory vesicles
2) Recycling endosome
3) Exosomes

51
Q

Effect of cellular alpha-synuclein release
1)
2)

A

1) Alpha-synuclein incorporated into other neurons, propagates
2) Alpha-synuclein stimulates astrocytes, microglia to release neurotoxic factors

52
Q

Effect of injecting M83 brain lysate on lifespan

A

Decreases lifespan

The earlier it is injected, the more severe resulting disease is

53
Q

Alpha-S pathological aggregates

A

Lewy bodies

54
Q

Parkin pathological aggregates

A

Substantia nigra degeneration, occasionally Lewy bodies

55
Q

PINK1 pathological aggregates

A

Lewy bodies found

56
Q

DJ-1 pathological aggregates

A

No pathology reported

57
Q

ATP13A2 pathological aggregates

A

Lewy bodies found

58
Q

LRRK2 pathological aggregates

A

Usually Lewy bodies

59
Q

Alpha-synuclein mutation ages of onset
1)
2)
3)

A

1) Dominant point mutations - onset 30-60 years
2) Duplicaiton onset 40-50 years
3) Triplication onset 30 years

60
Q

Parkin inheritance and onset

A

Recessive

Age of onset ~10-50 years

61
Q

PINK1 inheritance and onset

A

Recessive

Age of onset ~30-50 years

62
Q

DJ-1 inheritance and onset

A

Recessive

Age of onset ~20-40 years

63
Q

ATP13A2 inheritance and onset

A

Recessive

Age of onset ~10-22 years

64
Q

LRRK2 inheritance and onset

A

Dominant

Age of onset ~30-50 years

65
Q

How commonly do Parkin mutations lead to PD?

A

Second most common cause of L-dopa responsive PD

66
Q

Type of mutation in Parkin that leads to PD

A

Loss of function

67
Q

Parkin funciton

A

Cytosolic protein that acts as a ubiquitin ligase in the ubiquitination/protein degradation pathway

68
Q

How do Parkin mutations lead to PD?

A

Thought that defective ubiquitination/protein degradation system leads to buildup of non-ubiquitinated substrates.

Intracellular buildup of misfolded proteins affects neuron function

69
Q

Number of identified Parkin mutations

A

Over 100

70
Q

What is PINK1?
1)
2)
3)

A

1) A 581aa protein
2) N-terminal mitochondrial targeting motif
3) Converted kinase domain

71
Q

Effect of PINK mutations

A

Loss of function of kinase domain

Doesn’t affect PINK1/TRAP1 binding, co-localisation to mitochondria

72
Q

PINK1 substrate

A

TNF receptor-associated protein 1 (TRAP1)

73
Q

Normal PINK1/TRAP1 function
1)
2)

A

1) TRAP1 is a mitochondrial chaperone protein

2) PINK1 phosphorylates TRAP1 in response to oxidative stress

74
Q

Most common cause of autosomal dominant parkinsonism

A

LRRK2

75
Q

LRRK2 function

A

Not known
Contains a MAPKKK-class protein kinase domain
Promotes mitochondrial fragmentation

76
Q

Effect of mutation of LRRK2

A

Increases mitochondrial fragmentation

Increased kinase activity

77
Q

Number of identified LRRK2 mutations

A

20

78
Q

Number of identified DJ-1 mutations

A

10

79
Q

DJ-1 role
1)
2)

A

1) Modulating oxidative stress response

2) Mitochondrial function

80
Q

What does DJ-1 do during oxidative stress?

A

Translocates to mitochondrial outer membrane

81
Q 
Modulation pathways of alpha-synuclein accumulation
1)
2)
3)
4)
A

1) Glucoscerebroside from lysosome
2) Proteasome
3) Golgi fragmentation
4) Toxins

82
Q

Glucoscerebroside effect on PD
1)
2)
3)

A

1) In lysosome, glucoscerebrosidase converts glucoscerebroside to ceramide
2) Glucoscerebroside stabilises alpha-synuclein oligomers
3) If a defect occurs in glucoscerebrosidase, too much glucoscerebroside results in greater alpha-synuclein aggregation

83
Q

Mutations affecting proteasome funciton

A

Parkin

84
Q

Mutations leading to Golgi fragmentation

A

LRRK2 mutations

85
Q

Effect of alpha-synuclein on mitochondria

A

Interacts with and inhibits complex 1 of electron transport chain

86
Q

Proteins that inhibit mitochondrial fragmentation
1)
2)
3)

A

1) PINK1
2) DJ-1
3) Parkin

87
Q

Proteins that promote mitochondrial fragmentation
1)
2)

A

1) Alpha-synuclein

2) LRRK2

Molecule to Malady (35 decks)

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