Regeneration strat: Parkinsons Flashcards
What is Parkinson’s disease?
A highly prevalent neurodegenerative disorder
What is Parkinson’s characterised by?
Motor dysfunction
AND
Non-motor symptoms
What is the pathology of Parkinson’s
- Degeneration (dysfunction and death) of dopamine neurons in the substansia nigra (nigrastriatal neurons in the basal ganglia)
- Also in other areas
What occurs in normal basal ganglia?
- Cells of the SN produce and released dopamine
- Dopamine especilally affects the dorsal striatum (caudate and putamen)
- Dorsal striatum is involved in motor fucntion
What does dopamine do?
- Transmits signals between the areas of the brain which coordinate smooth and balanced muscle movement
- Controls functions related to mood
What are prescribed to patients with Parkinson’s disease?
- Dopamine precursors
(the brain coverts them to dopamine - Dopamine agonists
(Directly stimulate nerves in the brain which are not naturally stimulated by dopamine)
Where do the inouts to the basal ganglia go through?
The striatum
Where do the outputs from the basal ganglia go to?
The globus palladus and the substansia nigra pars reticula
What are the inhibitory connections in the basal ganglia circuitry?
GABA
What are the excitatory connections in the basal ganglia circuitry?
Glutamate
Describe the basal ganglia circuitry in normal people
When there is cortical input:
- Cortex activates the stratum (caudate and putamen
- Stratum inhibit the globus pallidus and substansia nigra pars reticular, inhibiting the normal inhibition of the thalamus
- Thalamus can then activate the cortex
What happens to the basal ganglia circuitry in Parkinson’s?
- Inputs provided by the substansia nigra are diminished
- More difficult to generate the transient inhibition from the striatum
- Results in TONIC inhibition from the globus pallidus to the thalamus
- Reducing thalamic excitation of the motor cortex
What are the characteristic motor symptoms of Parkinson’s?
- Slowness of movement
- Decreased spontaneous movements (eg. blinking)
- Tremors
- Muscle ridgity
- Drooping eyelids/ open mouth
- Tremor of hands
- Hunched over (postural changes)
- Slow, shuffling gait
What are the non-motor symptoms of Parkinson’s?
- Bowing of shoulders
- Swelling of feet
- Depression, sleep disorders
- Weight loss
- Excessive salivation
- Respiratory problems
- Orthostatic hypotenstion
- Increased sweating
- Constipation
What are the Braak stages of Parkinson’s?
Characterised by the spread of Lewy bodies which effect the brain in different ways
Stage I and stage II:
- Non-motor signs
Stage III:
- Motor signs
Stage IV, V, VI:
- Cognition and emotion signs
What is the pathology of Parkinson’s?
Lewy bodies composed of:
- Alpha-synuclein
- Ubiquitin
- Neurofilament
- Alpha B crystalin
Effect the chemicals in the brain
What dopamine precusor is used to treat Parkinson’s?
Levodopa (L-DOPA)
- Precursor to dopamine and can be converted by the neurons to dopamine
- Can cross the blood-brain barrier, unlike dopamine (dopamine can’t get into the brain where it is needed)
- Turned into dopamine in the brain
What are the problems with treating Parkinson’s with L-DOPA and how is this overcome?
- L-DOPA can be metabolised
- So prescribed with carbidopa (inhibits dopamine metabolism)
- Extended use can cause dyskinesias (uncontrolled movements - twitching, shaking etc)
How do dopamine agonists treat Parkinson’s and how are they used?
- Act like dopamine but not metabolised into dopamine
- Usually used with L-DOPA in young patients
- Similar side effects to L-DOPA but less involuntary movements
- Can cause hallucinations
What else can be used to treat Parkinson’s?
- MAO and COMT inhibitors
- Inhibit dopamine degredation
- Anticholinegics
What is thalamotomy and why is it used?
- Destruction of small parts of the thalamus in attempt to treat Parkinson’s
- Thalamus relays messages and sensations
What negative things can thalamotomy cause?
Slurred speech and coordination problems
What is pallidotomy and why is it used?
- Destruction of small parts of the globus pallidus
- Interrupts the pathways between the globus pallidus and the thalamus
- Stops the inhibition of the thalamus
What is deep brain stimulation?
- Pacemaker-like units
- Electrodes implanted into the subthalamic nucleus
- Used in Parkinson’s disease
- Can be turned on or off
How can cell replacement be used to treat Parkinson’s?
- Parkinson’s is due to a loss of a specifc cell type
Can transplant either:
- Similar cells that can make dopamine
OR - Other cells which make dopamine
- BUT must have a source of cells and must be able to transplant them into the brain
Could function in be restored in Parkinson’s disease using cell replacement? How?
YES
- Using human foetal mesencephalic tissue transplantation
- 6-9 week old human foetuses contain dopamanergic neurons
Trials showed:
- Neurons can suvive and re-inervate the striatum in transplanted rats
- Shows an increase in 17F-DOPA uptake in putamen
- In most successful cases, L-DOPA can be withdrawn and major symptomatic recovery is seen
What does using hPSCs in treatment of Parkinson’s depend upon?
1) If you can differentiate the PSCs to the correct cell type, ideally efficiently
2) That the cell type made is physiologically mature (
How can dopaminergic neruons be made from pluripotent stem cells?
1) Supress mesendoderm (promote ectoderm)
- Inhibit BMP and TGFbeta signalling
2) Then. must take through stages of development to get specific neural cells
What factors are needed to caudalize (tail end) the embryonic brain?
WNT
FGF
RA
What do the cells at the midbrain/hindbrain boundary produce?
Wnt1
FGF8
What does WNT signalling lead to? How?
- Precise patterning to the forebrain, midbrain, hindbrain and the anterior spinal cord
- In a dose dependant manner
What defines the fate of a neuroectodermal precursor on the D/V axis?
Shh, BMP, WNT
More shh = more ventral fates
More BMP or WNT = More dorsal fate
What is characteristiic of midbrain cells?
How is this achieved experimentally?
FOXA2+/ LMX1A+ dual expression
Achieved by the use of a GSK3b inhibitor and SHH/FGF8
What are the steps of a clinical trial using iPSC?
1) Clinical grade iPSC productin
2) Selection of ‘ideal’ neurons with no oncogenic risk
3) Selection of appropriate patients who may maximally benefit
4) Clinical monitoring and outcome assessment
5) Treatment alternatives for failed trial subjects
How are midbrain dopaminergic neurons specified?
1) Must specify along the AP axis
- By expressing specific concentrations of WNT, RA, FGF
2) Pattern along the DV axis
- Lots of shh
- Small bit of BMP/WNT
Where do dopaminergic neurons form along the DV axis of the midbrain?
At the very ventral part
