Lecture 23 - Parkinson's Disease Flashcards
What are the clinical symptoms of Parkinson’s disease?
1. Motor • Slowness • Stiffness • Tremor • Postural instability • Stooped, shuffling gait • Decreased arm swing when walking • Swallowing difficulty • Immobile facial expressions
2. Cognitive • Mood changes • Depression • Anxiety • Pain • Tiredness • Confusion
3. Sensory • Numbness • Aching • Pain • Anosmia
- Autonomic
• Hot/cold sensations
• Constipation
What is lost in PD?
Substantia nigra dopaminergic neurons in midbrain
Specifically:
• Ventrolateral area of SN
• i.e. the part where the neurons that extend to the striatum are
At what point does PD present?
60-70% of SN dopamineragic cells are lost
What is the function of the SN?
- Control of voluntary movement
* Production of dopamine
What is the function of dopamine?
- Regulation of mood
* Planning and modulation of movement
Where is the SN?
In the midbrain
Part of the basal ganglia
What are the basal ganglia?
What is it made up of?
Collection of nuclei in the white matter of the cerebral cortex Made up of nuclei: • Striatum: - Putamen - Caudate nucleus • Globus pallidus • SN: - Pars reticulate - Pars compacta • Subthalamic nuclei
What are the two parts of the SN?
Which is affected in PD?
Pars compacta
Pars reticulata
Pars compacta is made up of the large pigmented neurons that project to the striatum
These are the neurons that are affected
Describe the connectivity of the SN
Dopaminergic neurons project to striatum
Release dopamine onto these neurons → control of movement
What causes PD?
1. Sporadic / idiopathic • the majority Suggested mediators: • Toxins (such as pesticides) • Metals • certain drugs e.g. MPTP, a recreational drug
2. Familial Number of genes identified: • α-synuclein (SNCA) • Parkin • Leucine rich repeat kinase • DJ-I • PINK1
What pathological features are typical of PD?
Lewy bodies:
• Intracellular inclusions of protein
Lewy neurites
• similar to Lewy bodies
What is the composition of Lewy bodies?
α-synuclein
What is important about the structure of α-synuclein?
Natively unfolded
Basic domain:
• Rich in basic amino acids
α-helical formation
TM domain:
• Hydrophobic region
Acidic domain:
• mainly negatively charged
What is the function of α-synuclein?
Linked to: • Learning • Development • Synaptic plasticity • Regulation of vesicular transport & dopamine release
When does Lewy body accumulation start?
Proposed that it is well before diagnosis
Normally starts to accumulate outside the SN
Only diagnosed once accumulating in the SN
Which factors modulate the aggregation of α-synuclein?
i.e., what promotes and what inhibits aggregation?
Promotion: • α-syn over-expression • mutation in α-syn • Fe • Oxidants • Environmental toxins
Inhibition:
• Dopamine
What is the role of α-synuclein and metals?
Metals can promote the aggregation of α-synuclein
What is the interaction between α-synuclein and dopamine?
Dopamine induce α-synuclein oligomers are not Thioflavin T reactive
Describe the α-synuclein aggregation pathways with and without dopamine
- W/o dopamine:
α-syn monomer → α-syn oligomer → insoluble α-syn fibrils (ThT positive) → Lewy bodies - W/ dopamine:
α-syn monomer → soluble α-syn oligomers (ThT negative)
What is the inheritance of α-synuclein mutation?
Dominantly inherited
What happens in α-synuclein mutation?
Describe how this could lead to disease
Copy number variation: duplication & triplication of the gene
→ Over-expression of α-synuclein
Increased α-synuclein concentration promotes aggregation
What mouse models have been used to study PD?
- Mutant human α-synuclein
- Over-expression of wild type α-synuclein
- Intracerebral α-syuclein inoculation
What is observed in mice with mutant human α-synuclein?
What is the significance of this?
• Lewy bodies in brain
• Motor deficit
→ Substantiates the theory that α-synuclein causes motor deficits in PD in humans
What is observed in mice with over-expression of wild type α-synuclein?
- Lewy body formation
- Reduced striatal tyrosine hydroxylase levels (→ decreased dopamine)
- Movement disorder: less time spent on rotorod
Describe the propagation of α-synuclein observed in mice studies
What is the significance of this?
When α-synuclein is inoculated intracerebrally, there is rapid, progressive neurodegeneration observed
This study was done in mice
Mutant α-synuclein from symptomatic mouse injected into non-symptomatic mouse:
• Reduced life span
• Spreading of α-synuclein from area of injection to other regions
→ Indicated that α-synuclein spreads and propagates throughout the brain once present in PD
This may be what is seen in the Braak staging
Describe the cellular release and uptake of α-synuclein
- Through secretory vesicles
- Multi-vesicular bodies → released in exosomes
- Recycling endosome: release contents out into extracellular space
The neurons are not dying, but rather are viable
One neurone can deposit α-synuclein into the extracellular space (monomeric or aggregated) and it can be taken up by other cells
e.g.
• Astrocytes take it up → inflammation
• Taken up by other neighbouring neurons → propagation
Is Parkin mutation a significant cause of Parkinsonism?
2nd most common genetic cause of Parkinsonism
What is the function of Parkin?
What is the proposed role in PD?
What type of mutation is it: loss / gain of function ?
• Cytosolic protein
• Role in clearance of protein:
- cellular ubiquitination / protein degradation pathway
• i.e. it acts as ubiquitin ligase
Role in PD • Loss of Parkin • Non-ubiquitinated substrates accumulating in neurons • Altered protein turn-over → SN degeneration
• Autosomal recessive, loss of function mutations
What is the function of PINK1?
What is the proposed role in PD?
Normal function:
• Phosphorylation of TRAP1
• TRAP1 is a mitochondrial chaperone protein
Increased phosphorylation of TRAP1 under oxidative stress
In PD:
• Mutations leads to loss of kinase activity
Compare the inheritance of the following: • SNCA • Parkin • PINK1 • LRRK2 • DJ-1
SNCA: Autosomal dominant
Parkin: Autosomal-recessive
PINK1: Autosomal recessive
LRRK2: Autosomal dominant
DJ-1: Autosomal recessive
What is the function of LRRK2?
What is the proposed role in PD?
Precise function unknown
• Role in intracellular signalling? (its kinase domain is of the MAPKKK class)
• Promotion of mitochondrial & golgi fragmentation
PD:
• Mutation → Increased kinase activity
• Increased mitochondrial and golgi fragmentation
What is the function of DJ-1?
What is the proposed role in PD?
Function:
• Unknown
• Involved in modulating the oxidative stress response and mitochondrial function
• Oxidative stress → DJ-1 translocated to outer mitochondrial membrane
In PD:
• Unknown
Describe the causal spectrum of PD
Familial ←————→ Sporadic
Genetic variants ←–→ Environment
The more dominant the genetic variant, the less role the environmental needs to play
Describe the interaction of the mitochondria and α-synuclein
α-synuclein interacts with and inhibits Complex I of ETC
→ fragmentation
→ neuronal death
PINK1, DJ-1 and Parkin all interact with the mitochondria
Mutation in the genes for these proteins can lead to mitochondria dysfunction
→ Energy loss from cell
→ Cell death
Is the presence of Lewy bodies diagnostic for PD?
No
What is Braak staging?
Stages of PD based on where the Lewy bodies are deposited
6 stages
Location of Lewy bodies:
Stage 1: in dorsal motor nucleus of vagal nerve
→ olfactory structures
Stage 2: Lower raphe nuclei
→ stress and panic responses
Stage 3: SN
→ clinical diagnosis
Stage 4: temporal mesocortex
→ memory and emotions
Stage 5: temporal neocortex
→ memory and language
Stage 6: Neocortex
→ primary sensory areas
Progressive deposition of Lewy bodies
Location of deposition relates to the clinical features seen at that time
What is the significance of Thioflavin T reactive material?
Signifies aggregation of α-synuclein into amyloid plaques
What is the effect of dopamine on pre-formed, insoluble α-synuclein fibrils?
Can reverse the aggregation and make it soluble
What is the effect of point mutation in the gene for α-synuclein?
Alters the aggregating properties
For example:
• Aggregates more quickly (shortened lag phase)
• Reaches a high level of aggregation
What is the function of tyrosine hydroxylase?
What is the significance?
Enzyme for synthesis of dopamine
In transgenic mice that were over-experssing α-synuclein:
• Reduced levels of this enzyme
→ Reduced dopamine
Describe the propagation of recombinant α-synuclein
Recombinant :
from bacteria, i.e. has never been in a brain before
When the recombinant α-synuclein was injected into asymptomatic, non-transgenic mice it spread to other regions
Describe the change in life span observed in mice injected with mutant α-synuclein brain lysate
Injected mice: die at around 280 days
• If injected very early (at birth) there is even sooner onset of death
Non-injected mice: around 470 days
Injection of the brain lysate reduces the life span of the transgenic mice
In homozygous Parkin mutation, what is the age of onset of PD?
10-50 years: i.e. juvenile PD
What is the age of onset of sporadic PD?
70-80 years
Later than the familial causes
Describe the role of glucoscerebroside in PD
Glucoscerebroside stabilises α-synuclein oligomers
Normally it is broken down into ceremide in lysosomes
Mutations in the protein that break down glucoscerebroside lead to increased α-synuclein aggregation
What factors intracellularly can lead to α-synuclein aggregation?
- Parkin: decreased protein degradation
- LRRK2: Golgi fragmentation
- Glucoscerebroside: stabilisation of α-synuclein oligomers
- LRRK2: Mitochondria fragmentation → energy loss from cells
