what is the pathology of parkinsons disease?
degeneration of dopamine neurons in the substantia nigra (and other areas; olfactory)
what is parkinsons disease?
- highly prevalent neurodegenerative disorder
- characterised by motor dysfunction and non motor symptoms
where is the highest incidence of parkinsons disease seen and the mean age of onset?
- seen most in older people
- age of onset = 57
parkinsons involves death of nigrastriatal neurons of the basal ganglia, what is the function of the cells in a non-affected basal ganglia?
- cells of the SN produce+ release dopamine
- dopamine affects other centres
- main centres affected = dorsal striatum
- dorsal striatum involved in motor function
2 functions of dopamine
1) transmits signals between the areas in the brain that when working normally coordinate smooth and balanced muscle movement
2) control functions related to mood
what are dopamine precursors and antagonists?
precursors = medication the brain converts to dopamine
antagonists = directly stimulate nerves in the brain that are not naturally being stimulated by dopamine
- have been prescribed to patients and shown some effect
why is the basic circuit in the basal ganglia important?
- if you remove parts of the circuit it will mess it up
- causes sustained inhibition to the thalamus
what does wrong in parkinsons?
cells of substantia nigra degenerate - no longer producing adequate amounts of dopamine - neurons of striatum are no longer well regulated and do not behave normally - resulting in symptoms of parkinsons
what are motor symptoms of parkinsons?
1) slow movement
2) tremors
3) muscle rigidity
4) postural change
5) decreased spontaneous movements e.g. blinking
6) gait disorders - slow steps
what are non - motor symptoms of parkinsons?
1) depression
2) bowel problems
3) increased sweating
4) weight loss
5) excess salivation and repsiratory problems
what is a lewy body and effects?
- parts of the brain affected by parkinsons
- as the disease progresses the lewy bodies spread - as more of the cortex is affected the affects of the diseases are more severe
describe treatment of parkinsons with levodopa (L-DOPA)?
- converted by neurons to dopamine
- can cross blood-brain barrier (dopamine cannot)
- L-DOPA can be matabolised therefore prescribed with carbidopa which inhibits dopamine metabolism
- can produce dyskinesias (uncontrolled movements) and other side effects
describe treatment with dopamine agonists?
- not metabolised into dopamine but act like dopamine
- used with L-DOPA in young patients
- similar side effects to L-DOPA but less involuntary movements - cause hallucinations
what can be give to stop dopamine degradation?
inhibitors
what is thalamotomy surgery?
- destruction of small parts of the thalamus which relays messages/sensations
- can caused slurred speech / coordination problems
what is pallidotomy srugery?
- destruction of small parts of the globus pallidus
- interrupts pathways between globus pallidus and thalamus
what is deep brain stimulation and an advantage?
- pacemaker like units
- stimulate parts of the brain to calm down tremors
advantage over surgery it is reversible(can be switched off)
describe human foetal cell transplantation
- 6-9 week old human foetuses contain dopamanergic neurons
- these neurons can survive, re-inervate the striatum
- difficult operation and unethical
- increase in dopa uptake seen
- some patients had improvement 18 years post-grafting
- proof of principle that cell transplantation works
where else can you find dopamine producing cells?
pigmented retinal epithelium
what are 2 factors which treatment of parkinsons by PSCs depends on?
1) you can differentiate the PSCs to the correct cell type, ideally efficiently
2) the cell type you make needs to be physiologically mature
how would you manufacture pluripotent stem cells?
either derived from blastocyst or induced pluripotent stem cells
once you have worked out the factors needed to get the correct cells differentiated and you have the neural epithelium what has the happen?
- have to go through the correct neurogenesis
- create cultures of specific part of midbrain where dopaminergic neurons form
2 things which need to be done to make dopaminergic neurons from pluripotent stem cells?
1) supress meso/endoderm differentiation - promote ectoderm
2) inhibit BMP and TGFbeta signalling
