Lecture 22 - Parkinson's Disease Flashcards
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
Cognitive symptoms of PD 1) 2) 3) 4) 5) 6)
1) Mood changes
2) Depression
3) Anxiety
4) Pain
5) Tiredness
6) Confusion
Sensory symptoms of PD 1) 2) 3) 4) 5)
1) Numbness
2) Aching
3) Restlessness
4) Pain
5) Anosmia (loss of sense of smell)
Autonomic symptoms of PD
1)
2)
1) Hot/cold sensations
2) Constipation
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
Functions of substantia nigra
1)
2)
1) Controls voluntary movement
2) Produces neurotransmitter dopamine, which regulates mood
Where is the substantia nigra located?
Located in the midbrain
Part of the basal ganglia
What are the basal ganglia?
Clusters of neurons located in the white matter of the cortex
Components of the basal ganglia 1) 2) 3) 4)
1) Striatum (putamen, caudate)
2) Globus pallidus
3) Substantia nigra
4) Subthalamic nuclei
Two parts of the substantia nigra
1) Pars compacta
2) Pars reticulata
Pars compacta features
Large, pigmented neurons with neuromelanin
Pars reticulata features
Unpigmented neurons
What does the pars compacta primarily project to?
The striatum (caudate and putamen)
Role of striatum
Major role in planning and modulation of movement pathways
Area of substantia nigra most affected by PD
Most neuronal loss in venterolateral area of substantia nigra (this part projects to the striatum)
Name of pathway between substantia nigra and striatum
Nigrostriatal pathway
Suggested mediators of idiopathic PD
1)
2)
3)
1) Toxins (EG: pesticides)
2) Metals
3) Drug MPTP (byproduct of synthetic opiate MPPP)
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
Prevalence of Lewy pathology in non-symptomatic individuals over 60
5-20% of non-PD people over 60 have Lewy bodies
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
7xKTKEGV
1)
2)
3)
1) Region of alpha-synuclein
2) Rich in basic amino acids
3) High tendency for alpha helical formation
Non-Abeta component
1)
2)
3)
1) Also present in Abeta
2) Hydrophobic region
3) Region in alpha-synuclein
Acidic domain
1)
2)
1) Region in alpha-synuclein
2) Mainly negatively charged
Possible role of alpha-synuclein
Learning, development, synaptic plasticity associated with vesicles
Possible regulator of vesicle transport, dopamine release
Name for stages of PD based on Lewy body location
Braak staging
Stage 1 of Braak
Lewy bodies in dorsal motor nucleus of vagus nerve, anterior olfactory structures
Stage 2 of Braak
Lewy bodies in lower raphae nuclei, locus coeruleus
Locus coeruleus
Located in brainstem, controls responses to stress, panic
Stage 3 of Braak
Lewy bodies in substantia nigra, amygdala, nucleus basilis of Meynert
Stage 4 of Braak
Lewy bodies in temporal mesocortex
Stage 5 of Braak
Lewy bodies in temporal neocortex
Stage 6 of Braak
Lewy bodies in neocortex, primary sensory and motor areas
When in Braak stages do symptoms normally present?
Stage 3
Common way to detect alpha-synuclein amyloid deposits
Relative thioflavin T fluorescence
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)
Effect of metal presence on alpha synuclein aggregation
Increases aggregation
EG: FeCl3, etc
Effect of dopamine on alpha-synuclein oligomers
Alpha-synuclein monomers take ‘off’ pathway, forming non-thioflavin T reactive oligomers
How are mutations in alpha-synuclein inherited?
Autosomal dominant
Types of alpha-synuclein mutations
1)
2)
1) Malformed protein
2) Duplication of gene (leads to increased gene product)
Effect of A53T mutation
Alpha-synuclein mutation
Shorter lag phase in amyloidogenesis
Greater relative thioflavin T fluorescence by end of experiment
Effect of A30P mutation
Alpha-synuclein mutation
Shorter lag phase in amyloidogenesis
Same relative thioflavin T fluorescence by end of experiment as wild type
Effect of higher alpha-synuclein concentration
Increases aggregaiton
Phenotype of transgenic mice expressing A53T mutation
Motor deficit, Lewy body pathology
100% disease by 16 weeks
Phenotype of transgenic mice overexpressing human alpha-synuclein gene
Movement disorder
Promotor in alpha-synuclein gene in transgenic mice
Human platelet-derived growth-factor beta
Tyrosine hydroxylase
Enzyme involved in dopamine formation
Effect of alpha-synuclein overexpression on tyrosine hydroxylase
Tyrosine hydroxylase levels decrease, activity decreaess
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)
M83 mice
Transgenic mice overexpressing A53T alpha-synuclein gene
Neuronal release of alpha-synuclein
1)
2)
3)
1) Secretory vesicles
2) Recycling endosome
3) Exosomes
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
Effect of injecting M83 brain lysate on lifespan
Decreases lifespan
The earlier it is injected, the more severe resulting disease is
Alpha-S pathological aggregates
Lewy bodies
Parkin pathological aggregates
Substantia nigra degeneration, occasionally Lewy bodies
PINK1 pathological aggregates
Lewy bodies found
DJ-1 pathological aggregates
No pathology reported
ATP13A2 pathological aggregates
Lewy bodies found
LRRK2 pathological aggregates
Usually Lewy bodies
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
Parkin inheritance and onset
Recessive
Age of onset ~10-50 years
PINK1 inheritance and onset
Recessive
Age of onset ~30-50 years
DJ-1 inheritance and onset
Recessive
Age of onset ~20-40 years
ATP13A2 inheritance and onset
Recessive
Age of onset ~10-22 years
LRRK2 inheritance and onset
Dominant
Age of onset ~30-50 years
How commonly do Parkin mutations lead to PD?
Second most common cause of L-dopa responsive PD
Type of mutation in Parkin that leads to PD
Loss of function
Parkin funciton
Cytosolic protein that acts as a ubiquitin ligase in the ubiquitination/protein degradation pathway
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
Number of identified Parkin mutations
Over 100
What is PINK1?
1)
2)
3)
1) A 581aa protein
2) N-terminal mitochondrial targeting motif
3) Converted kinase domain
Effect of PINK mutations
Loss of function of kinase domain
Doesn’t affect PINK1/TRAP1 binding, co-localisation to mitochondria
PINK1 substrate
TNF receptor-associated protein 1 (TRAP1)
Normal PINK1/TRAP1 function
1)
2)
1) TRAP1 is a mitochondrial chaperone protein
2) PINK1 phosphorylates TRAP1 in response to oxidative stress
Most common cause of autosomal dominant parkinsonism
LRRK2
LRRK2 function
Not known
Contains a MAPKKK-class protein kinase domain
Promotes mitochondrial fragmentation
Effect of mutation of LRRK2
Increases mitochondrial fragmentation
Increased kinase activity
Number of identified LRRK2 mutations
20
Number of identified DJ-1 mutations
10
DJ-1 role
1)
2)
1) Modulating oxidative stress response
2) Mitochondrial function
What does DJ-1 do during oxidative stress?
Translocates to mitochondrial outer membrane
Modulation pathways of alpha-synuclein accumulation 1) 2) 3) 4)
1) Glucoscerebroside from lysosome
2) Proteasome
3) Golgi fragmentation
4) Toxins
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
Mutations affecting proteasome funciton
Parkin
Mutations leading to Golgi fragmentation
LRRK2 mutations
Effect of alpha-synuclein on mitochondria
Interacts with and inhibits complex 1 of electron transport chain
Proteins that inhibit mitochondrial fragmentation
1)
2)
3)
1) PINK1
2) DJ-1
3) Parkin
Proteins that promote mitochondrial fragmentation
1)
2)
1) Alpha-synuclein
2) LRRK2
