Parkinson's (finished) Flashcards
What are the 2 groups of brain diseases?
- Neurodegenerative
- Psychiatric
What are the characteristics of a neurodegenerative brain disease?
- Apoptosis/loss of neurones
- Disrupted/loss of (motor) function
- May also include changes in behaviour
- (e.g. AD, PD, prion disease)
What are the characteristics of a psychiatric brain disease?
- No obvious loss of neurones though may show some structural changes
- Developmental defects
- Change in behaviour
- (e.g. ADHD, ASD, SZ)
What are the 4 groups of movement disorders in the brain?
- Upper motor neuron disorders (cranium or SC)
- Lower motor neuron disorders (outside brain, muscle innervating neurons)
- Involuntary movement disorders (= dysfunction of basal ganglia)
- Cerebellar disorders
Name some upper MN disorders:
- Stroke
- Multiple Sclerosis
- Amytrophic lateral sclerosis (ALS)
Name some lower MN disorders:
- Peripheral neuropathy
- Myasthenia gravis
- Immune disease against nicotinic recpetors on muscles (NMJ)
Name some involuntary movement disorders:
- Parkinson’s disease
- Huntington’s disease
- Tremor
Name a cerebellar disorder:
Various tumor in any brain region will affect the health of the neurons present
(These cause motor dysfunction apparently)
Why is parkinsons considered to be a neurodegenerative disease?
incidence increases with age
Is parkinson considered mainly an early onset or late onset disease?
considered to be a late onset disease as most cases occur at older ages- but there is an early onset version of the disease which is predominantly caused by mutations within the genome
What is the prevalence of Parkinson’s disease?
Early onset:
40 - 60 yrs = 0.1%
>60 yrs = 0.5%
Late onset:
>85 yrs = 4%
How many patients have Parkinson’s in the UK?
Approx 125,000 ppl
Who is affected by Parkinson’s disease?
Affects all races & both sexes –> m/f at 3/2
As of 2019 - how many cases of Parkinson’s & how many deaths have there been?
8.5 million cases
330,000 deaths
How prevalent is Parkinson’s as a disabing disease?
2nd most common physically disabling disease of elderly after osteoarthiritis
(Most common neurological disabling disease)
What area is affected by Parkinson’s disease?
Neurodegeneration of extrapyramidal system
(mainly basal ganglia)
Name some symptoms of Parkinsons disease
= unable to perform normal motor function or initiate movement:
- Poor slow movement (Bradykinesia)
- Postural abnormalities
- Rigid posture
- Mask-like expression = unable to move face so do not have facial expressions
- Lack or rigidity of movement (Akinesia)
- Tremor at rest- reduces when undertaking voluntary movement
Name some later stage symptoms
Later stages also include = progression of the disease :
- Depression
- Dementia
- Endocrine dysfunction-tuberoinfundibular pathway responsible for prolactin release
What is the main neurochemical effect that causes the symptoms of parkinsons?
= Loss of striatal dopamine (single NT) within the basal ganglia
Describe the function of the basal ganglia
= programming movement
1. Stimulus to move
2. Assemble motor plan- select motor programme from memory stores + assemble appropriate sequences of motor programmes
3. Execute motor plan
Name the 4 dopamine pathways
- Nigrostriatal pathway
- Mesocortical
- mesolimbic pathways
- Tuberoinfundibular pathway
In what pathway, does parkinsons disease affect?
Nigrostriatal pathway- substantia nigra + dorsal striatum
What is the primary pathology of parkinsons disease?
Substantia nigra degeneration defined by loss of neuromelanin
What is neuromelanin?
Neuromelanin is a dark pigment found in large quantities in catecholaminergic cells of the substantia nigra pars compacta and locus coeruleus, giving a dark colour to the structures
Outline the list of changes occuring through parkinsons
- Dopamine in striatum ↓ (loss of 60-70% of dopaminergic neurons = motor symptoms)- nigrostriatal pathway = 1st characteristic of the disease
- Also loss of dopamine in mesolimbic areas (mood changes- depression, anxiety)
- Hypothalamic amines ↓= hypothalamus affected
- Cortical noradrenaline and ACh ↓ (cognitive loss)- cortical areas also affected as they are targets for dopaminergic neurons = further downstream effect within the pathogenesis
- Neuropeptides [spinal neurons, interneurons] in striatum ↓ (Substance P, Enkephalins) = neuronal dysfunction in neuroendocrine pathway
Name 2 imaging methods for diagnosing Parkinsons
PET
SPECT
What does PET stand for?
Positron Emission Tomography (PET)
How does a PET scan work in the diagnosis of Parkinsons?
Visualise and quantify dopaminergic neurones using radio-ligand (CIT) which bind to presynaptic dopamine transporter proteins (DAT)
Describe the difference in these PET scans
- Very strong signal in control
- Parkinsons brain = very strong reduction in the signal = little presynaptic DAT = indicates degeneration of neurons
What does SPECT stand for?
Single Photon Emission Computed Tomography
What is this SPECT scan showing?
Signal disappears over the period of disease progression = indicating loss of DAT = loss of presynaptic dopaminergic neurons
What is the main function of alpha-synuclein
modulates synaptic function
Describe the structure of a-synuclein and what is each structure responsible for?
Fairly small protein with 3 modular regions:
1. the N-terminal (green), responsible for interactions with membranes
2. the hydrophobic region (blue), relevant for aggregation of proteins which happens during neurodegeneration
3. the acidic C-terminal (red) involved in Ca2+ binding- responds to calcium and binds to it which affects its structure.
What changes α-synuclein affinity for cellular membranes?
Ca-dependency changes the affinity of α-synuclein for cellular membranes
More specifically what does α-synuclein do?
Alters SNARE complex formation and vesicle docking during the exocytosis process
Name the isoforms that α-synuclein can exist as and what can happen to them?
a-synuclein exists as monomeric, dimeric and heteromeric isoforms- molecules begin to aggregate = various forms of aggregates – which end up as lewy bodies
What are lewy bodies?
large aggregates within cells that are responsible for cell death
How is a-synuclein implicated in parkinsons?
a-synuclein = undergoes mutations which results in a pathway of aggregation leaving lewy bodies in neurons = cell death
How many compartments does a-synuclein act on at rest? + describe what it does in each compartment
At rest = 4-5 different compartments which a-synuclein is acting on neurotransmission:
- Inhibits DA synthesis by directly decreasing TH phosphorylation
- Aids in the sequestration of cytosolic DA by increasing the amount of VMAT on vesicles
- Prevents neurotransmitter release through interactions with synaptic vesicles and SNARE complex proteins to prevent trafficking and docking of vesicles
- Facilitates the recycling of synaptic vesicles by mediating membrane bending during endocytosis to (5) maintain numbers of vesicles.
Following an action potential, what does a-synuclein do?
- α‐syn rapidly disperses from the presynaptic terminal (2) providing unimpeded vesicular trafficking and exocytosis (release of neurotransmitter)
- The absence of α‐syn disinhibits TH and AADC, allowing DA synthesis to replenish DA released during synaptic transmission
What type of neuron is a-synuclein present in?
dopaminergic and glutamatergic
How do we know that a-synuclein modulates glutamatergic neurons
Different areas within the cerebellum stain different colours depending on what is present
- When merged (yellow) = strong localization between a-synuclein and VGluT1
= glutamatergic synapses are also affected and regulated by a-synuclein
Describe what a loss of a-synuclein causes at a dopaminergic terminal in parkinsons
loss/none of a-synuclein because most of it has aggregated =
1. Loss of α‐syn disinhibits TH and AADC, resulting in increased DA synthesis with a corresponding (2) decrease in VMAT levels
- Less dopamine in vesicles and more in cytosol = Unregulated trafficking of synaptic vesicles
- Loss of α‐syn function impairs endocytic vesicular recycling = Decrease in size of the vesicular pool
The net result is increased cytosolic DA, with a concomitant reduction of DA in synaptic vesicles.
Increased cytosolic DA auto‐oxidizes to produce reactive oxygen species (cytotoxic) and DA quinones
What is the net result of a-synuclein in a Parkinson’s disease cell?
- Inc cytosolic DA & red DA in vesicles
- Inc cytosolic DA auto-oxidises to produce reactive oxygen species & DA quinones
(DA auto-oxication = toxic to cell)
What other synapses does a-synuclein affect?
Glutamatergic synapses
(Too much glutamine is toxic to neuronal cells)
What is the result of a-synuclein acting on DA & glutamatergic neurones?
DA = dec DA release onto striatum
Glutamate = Inc glutamate release onto striatum (toxic to neuronal cells)
Striatal signalling is off = general reduction in synaptic activity
What area does dysfunctional striatal signalling affect & what is the cycle it creates?
Straitum signalling dysfunctional = inc a-synuclein on Cortex & SNr
Cortex = inc glutamate release that acts on striatum
SNr = dec DA release on striatum
= general reduction in synaptic activity
How was loss of a-synuclein tested in mice?
shRNA (small hairpin RNA) injected into SNr of brain & compared w control brain
Can knockout a-syn w shRNA - showed loss of DA neurons in the SNr compared to control brain
What are Lewy bodies & what do they cause?
Inclusions (aka aggregates) in interneurones with a core of a-syn aggregates
These aggregates form fibrils & contribute to the dementia seen in 50% of Parkinson’s patients
What are Lewy bodies caused by?
Mutations in proteins that cause hyper-phosphorylation
Where are the hotspots for Lewy bodies to form?
Substantia nigra & locus coeruleus
What is cell death from Lewy bodies due to?
Genetic
Environmental
- Oxidate stress
- Mitochonridal dysfunction
- Proteasome dysfunction
Can be a combination
What % of PD patients have a first-degree relative with PD?
15%
a-syn is the main factor for this, causing autosomal dominant early onset
What are the 5 genetic causes listed in this lecture?
1 - PARK1
2 - 5 mutations in a-syn gene
3 - PARK2
4 - PARK6
5 - Leucine-rich repeat kinase 2 (LRRK2)
What does PARK1 code for in relation to PD?
What typical signs does it show?
PARK1 locus codes SCNA (a-syn)
Autosomal dominant early onset PD w Lewy bodies & marked rigidity
What are the 5 mutations identified in the a-syn gene?
- A53T
- A30P
- E46K
- H50Q
- G51D
What does PARK2 code for in relation to PD?
What typical signs does it show?
PARK2 locus codes PRKN (Parkin) which is part of ubiquitin proteasome
Autosomal recessive early onset PD restricted SNr cell loss & NO Lewy bodies
What does PARK6 code for in relation to PD?
What typical signs does it show?
Locus codes PINK-1 (PTEN-induces kinase-1)
Cause autosomal recessive forms of PD
What does Leucine rich repeat kinase 2 (LRRK2) code for in relation to PD?
LRRK2 gene & SCNA gene mutations responsible for sporadic Parkinsonism
= higher risk factors
*SCNA gene codes for a-syn
How do the genes:
PARK1
PARK2
PARK4
PARK6
PARK7
impact on a-syn, causing Parkinson’s?
PARK1 & 4 = a-syn directly & indirectly interacts w mitochondria/vesicle release
PARK2 = Parkin (this is the gene) is a ligase, regulates mitochondria quality control thru mitophagy & mitochondria biogenesis
PARK7 = DJ-1 involved in cellular transformation, oxidative stress response & mitochondrial function
PARK6 = PINK-1 is a mitochondrial serine/tehronine-protein kinase that recruits Parkin to depolarised mitochondria for mitophagy
What are the 2 main environmental causes of PD?
- MPTP - drug induces neurodegeneration
- Herbicide exposure (e.g. paraquat)
How can exposure to herbicides (e.g. paraquat) cause PD?
- Herbicide is taken up by DA neurons (DAT)
- Creates oxidative stress
- Lead to cell deaths in DA pathways
What is MPTP?
How was it linked to PD?
It is a by-product of MPPP from opioids (drug abuse)
Some users of MPPP drug in 70s/80s found to developed PD later
How does MPTP cause PD?
MPTP is metabolised by MAO-B
Taken up by DA neurons (DAT)
Causes mitochondrial toxicity in almost exclusively DA neurons
Drugs are the main treatment for PD - why?
In PD there is a loss of terminal but not receptors
What sort of drugs are used to treat PD?
Drugs that enhance DA levels
As D2 receptors remain
Why can’t DA alone be given as a treatment for PD?
DA cannot pass the BBB so will not work
Why can’t L-DOPA be used to treat PD?
L-DOPA = precursor for DA - it can cross BBB
L-DOPA produces DA but also adrenaline & NA = side effects
What were the 3 options for treating PD?
1 - Dopamine
2 - L-DOPA
3 - Carbidopa
What is Carbidopa?
Used with L-DOPA to treat PD
It is a peripheral DOPA decarboxylase inhibitor
Why does carbidopa work as a treatment?
L-DOPA produces DA in brain
DOPA decarboxylase inhibitor in periphery prevents side effects (only active outside brain as cannot enter CNS)
What are the long term side effects of drugs that treat PD?
- Development of choric/involuntary movements ~2 years
- Rapid fluctuations clinical states “On-Off Effect”
- Nausea & anorexia (peripheral effect)
- Hypotension - not major problem
- Psychotic effects - mesocortical pathways
What are the long-term problems of L-DOPA therapy?
They cannot be effective for long periods of time
Tend to only word for 4-6 years (cannot be effective in long term)
What are the 4 other options to target instead of D2 receptors?
(This is in terms of L-DOPA therapy not lasting long)
- Target post-synaptic DA receptors to altered in PD
- D2 receptors are inhibitiory - main ones in basal ganglia, couples to Gai
- D1 receptors are excitatory - few in Basal ganglia, coupled to Gas
- Use D2 receptor agonists to treat the symptoms, esp in early onset, young patients
What is another treatment strategy that can be used when L-DOPA therapies stop working?
Ropinirol –> it works on human D2 like receptors
(D2, D3 & D4)
When is ropinirole used as a treatment?
Treatment used if L-DOPA treatment has failed
What is the order of potency of ropinirole on D2 like receptors?
D3 > D2 > D4
What are the 5 treatment strategies in PD?
1 - L-DOPA, using carbidopa as a peripheral inhibitor
2 - DA recepto D2 agonists (Ropinirol & Bromocriptine)
3 - Prevent DA metabolism
4 - Inc DA release by Amatidine
5 - Adeonsine A2A receptor agonist = improved add-on therapy with L-DOPA
What can be used to control tremor in PD?
Muscarinic receptor (GPCR_ agonists
What are the 3 possible options to prevent, delay or reverse neurodegeneration causing PD?
- Foetal neuronal transplantation (will stem cell degenerate again?)
- Promote neuronal survival/reinnervation, nicotinic receptor agonists
- Block target a-syn aggregation
What are the 3 types of drugs that prevent DA metabolism?
1 - Reuptake = DAT inhibitors (DAT degenerated in PD ) - not used
2 - Monoamine Oxidase = MAO-B inhibitors - selegiline
3 - Catechol-O-methyl transferase = COMT inhibitors
Inhibiting either/both MAO and COMT = just as beneficial as L-DOPA provision
- Blockers of enzymes = increase in dopamine
What are the 2 main targets in PD treatment?
1 - Target a-syn signalling
2 - Target DA signalling (DA levels OR DA receptor activation)
Describe how a-synuclein pathology has been used to develop different drugs
- a-synuclein pathology has been used to develop different drugs to reduce the amount of aggregating s-synuclein
1-Impairment of vesicle docking & recycling due to a-syn dysfunction prevents incorporation of newly synthesised & newly taken up DA into vesicles
2 - This leads to an inc in cytosolic DA conc (DAcyt) which causes inc generation of toxic reactive O2 species & ultimately contributes to DA neurodegeneration
