Lecture 22 - Parkinson's Disease

Question 1

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

Answer 1

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

Question 2

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

Answer 2

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

Question 3

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

Answer 3

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

Question 4

Autonomic symptoms of PD
1)
2)

Answer 4

1) Hot/cold sensations

2) Constipation

Question 5

Characteristic anatomical feature of PD

Answer 5

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

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

Question 6

Functions of substantia nigra
1)
2)

Answer 6

1) Controls voluntary movement

2) Produces neurotransmitter dopamine, which regulates mood

Question 7

Where is the substantia nigra located?

Answer 7

Located in the midbrain

Part of the basal ganglia

Question 8

What are the basal ganglia?

Answer 8

Clusters of neurons located in the white matter of the cortex

Question 9

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

Answer 9

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

Question 10

Two parts of the substantia nigra

Answer 10

1) Pars compacta

2) Pars reticulata

Question 11

Pars compacta features

Answer 11

Large, pigmented neurons with neuromelanin

Question 12

Pars reticulata features

Answer 12

Unpigmented neurons

Question 13

What does the pars compacta primarily project to?

Answer 13

The striatum (caudate and putamen)

Question 14

Role of striatum

Answer 14

Major role in planning and modulation of movement pathways

Question 15

Area of substantia nigra most affected by PD

Answer 15

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

Question 16

Name of pathway between substantia nigra and striatum

Answer 16

Nigrostriatal pathway

Question 17

Suggested mediators of idiopathic PD
1)
2)
3)

Answer 17

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

Question 18

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

Answer 18

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

Question 19

Prevalence of Lewy pathology in non-symptomatic individuals over 60

Answer 19

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

Question 20

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

Answer 20

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

Question 21

7xKTKEGV
1)
2)
3)

Answer 21

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

Question 22

Non-Abeta component
1)
2)
3)

Answer 22

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

Question 23

Acidic domain
1)
2)

Answer 23

1) Region in alpha-synuclein

2) Mainly negatively charged

Question 24

Possible role of alpha-synuclein

Answer 24

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

Question 25

Name for stages of PD based on Lewy body location

Answer 25

Braak staging

Question 26

Stage 1 of Braak

Answer 26

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

Question 27

Stage 2 of Braak

Answer 27

Lewy bodies in lower raphae nuclei, locus coeruleus

Question 28

Locus coeruleus

Answer 28

Located in brainstem, controls responses to stress, panic

Question 29

Stage 3 of Braak

Answer 29

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

Question 30

Stage 4 of Braak

Answer 30

Lewy bodies in temporal mesocortex

Question 31

Stage 5 of Braak

Answer 31

Lewy bodies in temporal neocortex

Question 32

Stage 6 of Braak

Answer 32

Lewy bodies in neocortex, primary sensory and motor areas

Question 33

When in Braak stages do symptoms normally present?

Answer 33

Stage 3

Question 34

Common way to detect alpha-synuclein amyloid deposits

Answer 34

Relative thioflavin T fluorescence

Question 35

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

Answer 35

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

Question 36

Effect of metal presence on alpha synuclein aggregation

Answer 36

Increases aggregation | EG: FeCl3, etc

Question 37

Effect of dopamine on alpha-synuclein oligomers

Answer 37

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

Question 38

How are mutations in alpha-synuclein inherited?

Answer 38

Autosomal dominant

Question 39

Types of alpha-synuclein mutations 1) 2)

Answer 39

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

Question 40

Effect of A53T mutation

Answer 40

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

Question 41

Effect of A30P mutation

Answer 41

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

Question 42

Effect of higher alpha-synuclein concentration

Answer 42

Increases aggregaiton

Question 43

Phenotype of transgenic mice expressing A53T mutation

Answer 43

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

Question 44

Phenotype of transgenic mice overexpressing human alpha-synuclein gene

Answer 44

Movement disorder

Question 45

Promotor in alpha-synuclein gene in transgenic mice

Answer 45

Human platelet-derived growth-factor beta

Question 46

Tyrosine hydroxylase

Answer 46

Enzyme involved in dopamine formation

Question 47

Effect of alpha-synuclein overexpression on tyrosine hydroxylase

Answer 47

Tyrosine hydroxylase levels decrease, activity decreaess

Question 48

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

Answer 48

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)

Question 49

M83 mice

Answer 49

Transgenic mice overexpressing A53T alpha-synuclein gene

Question 50

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

Answer 50

1) Secretory vesicles 2) Recycling endosome 3) Exosomes

Question 51

Effect of cellular alpha-synuclein release 1) 2)

Answer 51

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

Question 52

Effect of injecting M83 brain lysate on lifespan

Answer 52

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

Question 53

Alpha-S pathological aggregates

Answer 53

Lewy bodies

Question 54

Parkin pathological aggregates

Answer 54

Substantia nigra degeneration, occasionally Lewy bodies

Question 55

PINK1 pathological aggregates

Answer 55

Lewy bodies found

Question 56

DJ-1 pathological aggregates

Answer 56

No pathology reported

Question 57

ATP13A2 pathological aggregates

Answer 57

Lewy bodies found

Question 58

LRRK2 pathological aggregates

Answer 58

Usually Lewy bodies

Question 59

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

Answer 59

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

Question 60

Parkin inheritance and onset

Answer 60

Recessive | Age of onset ~10-50 years

Question 61

PINK1 inheritance and onset

Answer 61

Recessive | Age of onset ~30-50 years

Question 62

DJ-1 inheritance and onset

Answer 62

Recessive | Age of onset ~20-40 years

Question 63

ATP13A2 inheritance and onset

Answer 63

Recessive | Age of onset ~10-22 years

Question 64

LRRK2 inheritance and onset

Answer 64

Dominant | Age of onset ~30-50 years

Question 65

How commonly do Parkin mutations lead to PD?

Answer 65

Second most common cause of L-dopa responsive PD

Question 66

Type of mutation in Parkin that leads to PD

Answer 66

Loss of function

Question 67

Parkin funciton

Answer 67

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

Question 68

How do Parkin mutations lead to PD?

Answer 68

Thought that defective ubiquitination/protein degradation system leads to buildup of non-ubiquitinated substrates. Intracellular buildup of misfolded proteins affects neuron function

Question 69

Number of identified Parkin mutations

Answer 69

Over 100

Question 70

What is PINK1? 1) 2) 3)

Answer 70

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

Question 71

Effect of PINK mutations

Answer 71

Loss of function of kinase domain Doesn't affect PINK1/TRAP1 binding, co-localisation to mitochondria

Question 72

PINK1 substrate

Answer 72

TNF receptor-associated protein 1 (TRAP1)

Question 73

Normal PINK1/TRAP1 function 1) 2)

Answer 73

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

Question 74

Most common cause of autosomal dominant parkinsonism

Answer 74

LRRK2

Question 75

LRRK2 function

Answer 75

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

Question 76

Effect of mutation of LRRK2

Answer 76

Increases mitochondrial fragmentation | Increased kinase activity

Question 77

Number of identified LRRK2 mutations

Answer 77

20

Question 78

Number of identified DJ-1 mutations

Answer 78

10

Question 79

DJ-1 role 1) 2)

Answer 79

1) Modulating oxidative stress response | 2) Mitochondrial function

Question 80

What does DJ-1 do during oxidative stress?

Answer 80

Translocates to mitochondrial outer membrane

Question 81

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

Answer 81

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

Question 82

Glucoscerebroside effect on PD 1) 2) 3)

Answer 82

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

Question 83

Mutations affecting proteasome funciton

Answer 83

Parkin

Question 84

Mutations leading to Golgi fragmentation

Answer 84

LRRK2 mutations

Question 85

Effect of alpha-synuclein on mitochondria

Answer 85

Interacts with and inhibits complex 1 of electron transport chain

Question 86

Proteins that inhibit mitochondrial fragmentation 1) 2) 3)

Answer 86

1) PINK1 2) DJ-1 3) Parkin

Question 87

Proteins that promote mitochondrial fragmentation 1) 2)

Answer 87

1) Alpha-synuclein | 2) LRRK2