Lecture 22 - Parkinson's Disease Flashcards Preview

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Flashcards in Lecture 22 - Parkinson's Disease Deck (87):
1

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

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

2

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

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

3

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

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

4

Autonomic symptoms of PD
1)
2)

1) Hot/cold sensations
2) Constipation

5

Characteristic anatomical feature of PD

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

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

6

Functions of substantia nigra
1)
2)

1) Controls voluntary movement
2) Produces neurotransmitter dopamine, which regulates mood

7

Where is the substantia nigra located?

Located in the midbrain
Part of the basal ganglia

8

What are the basal ganglia?

Clusters of neurons located in the white matter of the cortex

9

Components of the basal ganglia
1)
2)
3)
4)

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

10

Two parts of the substantia nigra

1) Pars compacta
2) Pars reticulata

11

Pars compacta features

Large, pigmented neurons with neuromelanin

12

Pars reticulata features

Unpigmented neurons

13

What does the pars compacta primarily project to?

The striatum (caudate and putamen)

14

Role of striatum

Major role in planning and modulation of movement pathways

15

Area of substantia nigra most affected by PD

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

16

Name of pathway between substantia nigra and striatum

Nigrostriatal pathway

17

Suggested mediators of idiopathic PD
1)
2)
3)

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

18

Genes involved in familial PD
1)
2)
3)
4)
5)

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

19

Prevalence of Lewy pathology in non-symptomatic individuals over 60

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

20

Alpha-synuclein protein structure
1)
2)
3)
4)

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

21

7xKTKEGV
1)
2)
3)

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

22

Non-Abeta component
1)
2)
3)

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

23

Acidic domain
1)
2)

1) Region in alpha-synuclein
2) Mainly negatively charged

24

Possible role of alpha-synuclein

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

25

Name for stages of PD based on Lewy body location

Braak staging

26

Stage 1 of Braak

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

27

Stage 2 of Braak

Lewy bodies in lower raphae nuclei, locus coeruleus

28

Locus coeruleus

Located in brainstem, controls responses to stress, panic

29

Stage 3 of Braak

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

30

Stage 4 of Braak

Lewy bodies in temporal mesocortex

31

Stage 5 of Braak

Lewy bodies in temporal neocortex

32

Stage 6 of Braak

Lewy bodies in neocortex, primary sensory and motor areas

33

When in Braak stages do symptoms normally present?

Stage 3

34

Common way to detect alpha-synuclein amyloid deposits

Relative thioflavin T fluorescence

35

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

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

Effect of metal presence on alpha synuclein aggregation

Increases aggregation
(EG: FeCl3, etc)

37

Effect of dopamine on alpha-synuclein oligomers

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

38

How are mutations in alpha-synuclein inherited?

Autosomal dominant

39

Types of alpha-synuclein mutations
1)
2)

1) Malformed protein
2) Duplication of gene (leads to increased gene product)

40

Effect of A53T mutation

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

41

Effect of A30P mutation

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

42

Effect of higher alpha-synuclein concentration

Increases aggregaiton

43

Phenotype of transgenic mice expressing A53T mutation

Motor deficit, Lewy body pathology
100% disease by 16 weeks

44

Phenotype of transgenic mice overexpressing human alpha-synuclein gene

Movement disorder

45

Promotor in alpha-synuclein gene in transgenic mice

Human platelet-derived growth-factor beta

46

Tyrosine hydroxylase

Enzyme involved in dopamine formation

47

Effect of alpha-synuclein overexpression on tyrosine hydroxylase

Tyrosine hydroxylase levels decrease, activity decreaess

48

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

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

M83 mice

Transgenic mice overexpressing A53T alpha-synuclein gene

50

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

1) Secretory vesicles
2) Recycling endosome
3) Exosomes

51

Effect of cellular alpha-synuclein release
1)
2)

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

52

Effect of injecting M83 brain lysate on lifespan

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

53

Alpha-S pathological aggregates

Lewy bodies

54

Parkin pathological aggregates

Substantia nigra degeneration, occasionally Lewy bodies

55

PINK1 pathological aggregates

Lewy bodies found

56

DJ-1 pathological aggregates

No pathology reported

57

ATP13A2 pathological aggregates

Lewy bodies found

58

LRRK2 pathological aggregates

Usually Lewy bodies

59

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

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

60

Parkin inheritance and onset

Recessive
Age of onset ~10-50 years

61

PINK1 inheritance and onset

Recessive
Age of onset ~30-50 years

62

DJ-1 inheritance and onset

Recessive
Age of onset ~20-40 years

63

ATP13A2 inheritance and onset

Recessive
Age of onset ~10-22 years

64

LRRK2 inheritance and onset

Dominant
Age of onset ~30-50 years

65

How commonly do Parkin mutations lead to PD?

Second most common cause of L-dopa responsive PD

66

Type of mutation in Parkin that leads to PD

Loss of function

67

Parkin funciton

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

68

How do Parkin mutations lead to PD?

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

Intracellular buildup of misfolded proteins affects neuron function

69

Number of identified Parkin mutations

Over 100

70

What is PINK1?
1)
2)
3)

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

71

Effect of PINK mutations

Loss of function of kinase domain

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

72

PINK1 substrate

TNF receptor-associated protein 1 (TRAP1)

73

Normal PINK1/TRAP1 function
1)
2)

1) TRAP1 is a mitochondrial chaperone protein
2) PINK1 phosphorylates TRAP1 in response to oxidative stress

74

Most common cause of autosomal dominant parkinsonism

LRRK2

75

LRRK2 function

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

76

Effect of mutation of LRRK2

Increases mitochondrial fragmentation
Increased kinase activity

77

Number of identified LRRK2 mutations

20

78

Number of identified DJ-1 mutations

10

79

DJ-1 role
1)
2)

1) Modulating oxidative stress response
2) Mitochondrial function

80

What does DJ-1 do during oxidative stress?

Translocates to mitochondrial outer membrane

81

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

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

82

Glucoscerebroside effect on PD
1)
2)
3)

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

Mutations affecting proteasome funciton

Parkin

84

Mutations leading to Golgi fragmentation

LRRK2 mutations

85

Effect of alpha-synuclein on mitochondria

Interacts with and inhibits complex 1 of electron transport chain

86

Proteins that inhibit mitochondrial fragmentation
1)
2)
3)

1) PINK1
2) DJ-1
3) Parkin

87

Proteins that promote mitochondrial fragmentation
1)
2)

1) Alpha-synuclein
2) LRRK2