Parkinson's Disease Flashcards
What percentage of people have Parkinson’s?
1% of people over 50.
What are the symptoms of Parkinson’s?
Resting limb tremor, akinesia, bradykinesia, rigidity.
Gradual loss of procedural memory - loss of ability to learn skills and habits.
Depression
Cognitive decline late in disease.
What is the neurochemistry of Parkinson’s?
Major reduction of dopamine levels in striatum.
Major reduction of dopamine levels in substantia nigra.
Reductions in noradrenaline and serotonin.
What is the primary finding in terms of pathology?
Loss of dopaminergic neurones in the substantia nigra pars (SNc).
40-80% loss of SNc neurones before movement symptoms appear.
Which regions other than SNc are affected?
Dopaminergic neurones of ventral tegmental area.
Nuclei of locus coeruleus and raphe nuclei.
What is the role of the SNc?
Processes and executes the information for movement.
What are the major histopathological sign?
Lewy bodies.
What are lewy bodies?
Intracellular protein deposits.
What are the conflicting views on Lewy bodies?
Traditional view is that Lewy bodies are a key part of the pathological process.
Recently, some have come to view them as part of a protective mechanism.
What are the predictive factors for parkinson’s?
Age
Family history
Head trauma
Which toxins can cause a parkinsonian syndrome?
MPTP
Rotenone
(Both mitochondrial toxins)
What is the action of MPTP?
It is specific to dopaminergic neeurones because it is taken up into DA cells by the dopamine transporter.
MPTP is converted to the active toxic species MPP+ within the mitochondrion by MAO-B.
MPP+ inhibits complex 1 of the mitochondrial electron transport chain.
Cells die rapidly because of low ATP levels and high free radical production. Apoptosis is induced.
Usually, no Lewy bodies form, although recent continuous MPTP infusion experiments have shown inclusion bodies in neurons.
What is rotenone?
A plant-derived pesticide commonly used in vegetable plots.
How does rotenone work?
Inhibits complex 1 of the mitochondrial electron transport chain.
Rats given long term doses of rotenone that cause partial inhibition of complex 1 develop parkinsonian symptoms and loss of dopaminergic neurones.
Proteins inclusions are found which are related to Lewy bodies in protein content.
Why are dopaminergic neurones particularly affected by mitochondrial inhibition?
Possibly because they’re continually under free radical stress due to their biochemistry.
The biochemical pathway of dopamine degradation produces free radicals.
What is the life cycle of dopamine (DA)?
It is synthesised in the cytoplasm.
It is rapidly transported into vesicles by VMAT2.
These progress to the axon terminals and plasma membrane.
After release DA is taken up again by DAT, the dopamine transporter.
DA is degraded by MAO-B in the mitochondrion.
Give two examples of environmentally caused parkinsonisms.
Ingestion of glutamate in poorly prepared local vegetables in Guam. - Causes excitotoxic cell death, not specific to dopaminergic neurones.
After WW1 a pandemic of encephalitis left many people with parkinsonian symptoms. Post mortem found severe loss of SNc dopamine neurones.
How many different forms of familial PD are known?
13
What are the genes responsible for Parkinson’s called?
PARK genes
Which genes are related to juvenile PD?
PARK 2 parkin
PARK 7 DJ1
Which genes are related to juvenile to early (20-40) PD?
PARK 6 PINK 1
PARK 9 ATP13A2
Which genes are related to early (40-60) PD?
PARK 1 (4 for triplication) SNCA1 alpha synuclein
PARK 3?
Some PARK8 LRRK2
Which genes are related to late PD?
PARK 5 UCHL1
NURR1/NR4A2
PARK8 LRRK2
PARK 13 HtrA2
Which protein does PARK 1 (SNCA1) encode?
α synuclein
What is the major protein in Lewy bodies?
α synuclein
Which mutations are repeatedly found in α synuclein?
Alanine30Proline (A30P)
Alanine53Threonine (A53T)
In another family triplication of the α synuclein gene caused PD.
What is the relationship between α synuclein and PD?
Too much α synuclein causes PD.
What is the experimental evidence linking α synuclein to PD?
- Human α synuclein was expressed everywhere in brain of transgenic mice. Led to:
- specific loss of DA neurone terminals.
- Movement disorder
- Protein inclusions form that have α synuclein and ubiquitin (like Lewy bodies) - Human α synuclein expressed in drosophila neurones - either all or specifically dopaminergic neurones
- specific cell death of dopaminergic neurones occurs in both cases
What is the normal function of α synuclein?
It is a pre-synaptic axon terminal protein.
It has a developmental role in synapse formation or stabilisation.
Maintains vesicle pool size and inhibits refilling the fast release of vesicle pool.
Stimulates dopamine transporter recycling.
Acts in the endocytosis pathway for synaptic vesicle recycling after fusion with the plasma membrane.
Membrane associated - occurs in protein complexes with synphilin 1, DJ 1 and other proteins.
Essential mediator of oxidative stress
How might mutant α synuclein affect dopamine?
Mutant α synuclein has reduced recycling, increased DAT in the plasma membrane, more DA uptake, and therefore may have higher cytoplasmic DA levels and more DA flow through the degradation system that produces free radicals.
What are the possible modes of action for mutant α synuclein?
- Causes defects in membrane transport, and indirectly ER stress - ER stress an cause apoptosis.
- Defects in membrane transport causes altered regulation of cytoplasmic dopamine levels - may act via DAT regulation.
- Damage to mitochondria via ER/ROS stress
- Aggregation directly leads to dopamine cell degeneration.
Which two PARK genes are involved in protein clearance?
PARK2 and PARK5
What does PARK2 encode?
Parkin - one of the E3 ubiquitin ligases.
What does PARK5 encode?
A ubiquitin carboxyl-terminal hydrolase.
What has parkin been shown to be important in clearing in mammalian cells?
α synuclein
What has parkin been shown to be important in clearing in Drosophila?
Synphilin 1 - a protein that interacts with synuclein and is present in Lewy Bodies
What is the evidence that parkin clears α synuclein?
Drosophila with human α synuclein expressed in the brain lose dopaminergic neurones.
Simultaneous co-expression of parkin reduces these neurones.
This supports the hypothesis that α synuclein is one of parkin’s client proteins for routine clearance via ubiquitination and proteolysis in the proteasome.
Therefore one way parkin mutants may act is to increase the α synuclein load of cells.
What kind of mutation is found in PARK6 (Pink1)?
Loss of function of a mitochondrial serine-threonine kinase.
What is the normal function of Pink1?
It is targeted primarily to mitochondria and protects them against stress.
It is an outer mitochondrial membrane protein with the kinase domain in the cytoplasm.
What is the effect of PARK6 -/- on mitochondria?
The mitochondria depolarise more under stress and more easily trigger cell apoptosis in response to cell stress.
Where are PARK7 mutations?
DJ1
What is DJ1?
A known oncogene with a role in oxidative stress responses.
Normal DJ1 is neuroprotective.
Normal DJ1 has been found in protein complexes with α synuclein.
Where is PINK1 in relation to parkin? What is the relvance of this?
PINK1 is upstream of parkin.
Parkin can rescue PINK1 mutants but not vice versa.
What are PINK1 and parkin required for?
Mitochondrial maintenance.
What effect does PINK1 have on parkin?
PINK1 phosphorylates parkin - this is essential for mitochondrial relocation of parkin and therefore for its anti PD effect in mitochondria.
Give examples of a PINK1 mutant animal model.
PINK1 KO mice show dopamine release defects and increased cytoplasmic dopamine (potentially toxic).
PINK1 KO mice neuronal mitochondria have structural and molecular abnormalities and are more sensitive to environmental oxidative stress.
How does DJ1 protect against mitochondrial toxins?
DJ1 loss of function makes flies hypersensitive to paraquat, rotenone and MPTP.
DJ1 overexpression protects against mitochondrial toxins.
DJ1 and PINK1 act together to determine MPTP resistance: mutant proteins fail.
DJ1 is a redox- sensitive molecular chaperone - it only acts in oxidising environments.
DJ1 is a chaperone for α synuclein…
Which gene causes a genetic disease indistinguishable from late onset PD?
PARK8
Which allele in PARK8 is responsible for 1% of sporadic or idiopathic PD and 2.5% of all PD in European populations?
G2019S
What is the frequency of PD due to PARK8 mutations in middle Eastern populations?
40%
What is PARK8?
A protein kinase
What else is PARK8 known as?
LRRK2
What is the inheritance pattern of LRRK2 PD mutations?
Dominant with reduced penetrance.
Gain of function mutation.
What does LRRK2 affect the aggregation of?
α synuclein and tau
What happens in Drosophila with LRRK2 loss of function?
Dopamine neuron shrinkage
Low tyrosine hydroxylase
Locomotion problems
No cell death.
What happens in Drosophila with LRRK2 overexpression?
Dopaminergic neuron death.
What is the consequence of loss of function PARK mutations?
Striatal dopamine release in KO mice.
How is Parkinson’s disease treated?
L-Dopa (converts to DA in dopaminergic neurons) (DA does not peneterate BBB)
Very effective at first, given with carbidopa/benserazide.
After 5 years of treatment only 20% of patients still responding.
