Parkinsons Disease Lecture 25 Flashcards
What are the symptoms of Parkinsons Disease?
Tremors - mainly occur when resting Rigid muscles –> difficult to move (walking, writing, speech) Bradykineasia: hard to initiate and execute movement
How is Parkinsons Disease degenerative?
Up to 2% of >65s affected Causes a decrease in the quality of life –> increased chance of dementia and death
Define an ideopathic disease?
Of unknown cause
Although parkinson’s is ideopathic what are the likely causes?
Combination of genetics and environment Symptomatic parkinsons can be post viral or drug related
What is the biochemical / pathological basis of parkinsons
Lesions in the basal ganglia (extra pyramidal system) Particularly in the substantia nigra (SN) and SN pars complex (SNpc). This is because it is the site of dopaminergic neurons which project to the striatum. - Important for movement and initiation
What are the differences in the SNpc in the disease compared to normal?
Loss of dopamine from SNpc and striatum. –> loss of striatum innervation (50% of dopaminergic cells, 80% of dopamine) Degeneration of dopaminergic neurons in SNpc - Loss of dopaminergic receptors (GPCRs)
What are the consequences of Parkinsons Disease?
D1 (G_alpha_s) and D2 (G_alpha_i) receptors are required for movement initiation. –> decreased feedback to thalamus
Describe the histopathology of the disease
Loss of cells in the substantia nigra Lewy bodies are produced, containing lipds, proteins and alpha-synuclein (leads to aggregation, ubiquitin)
What is the purpose of synuclein?
Normally regulates dopaminergic neurotransmission and synaptic vesicle pools, protects nerve terminal from injury
What does the presence of Lewy bodies suggest?
A build up of toxins –> cell death (5% per decade)
What are the inheritable effects of Parkinsons?
Production of Lewy bodies –> pathogenesis, causes a change in the ubiquitin-proteasomal pathway
Describe the ubiquitin-proteasomal pathway enzymes:
Leads to protein degradation - Ubiquitin is the signalling molecule which signals for degradation. Turns it into a heritable disease
What is the normal cause of cell death
What happens to synuclein in the onset of parkinsons disease?
Acquires toxic properties. This causes misfolding in the ER –> disruption of organelles –> disruption of function
What are the four therapy stategies for treating parkinson’s disease?
Drugs that replace dopamine –> increased synthesis Drugs that mimic dopamine Drugs which reduce dopamine metabolism Surgery
How is dopamine usually synthesised
Tyrosine –> DOPA –> dopamine Tyrosine hydroxylase is the rate limiting enzyme
What drugs are used to replace dopmaine.
L-DOPA because it increases dopamine synthesis –> increased release whilst ignoring the rate limiting enzyme.
What are the problems with L-dopa therapy?
Less than 1% of synthesised dopamine reaches the brain despite a 95% conversion rate. Side effects: involuntary jerky movements, nausea, hypotension, anorexia, confusion, disorientation, insomnia, schizophrenia like. Off and on pattern
What are possible ways to improve L-dopa therapy?
-Inhibit peripheral DOPA decarboxylase in order to increase the dopamine enetering the brain - Block peripheral DOPA receptors - Inhibit dopamine metabolism - Delay use
How do drugs which mimic dopamine treat parkinsons?
Dopamine receptor agonists –> can still be used when the dopaminergic neurons are lost
How do drugs which reduce dopamine metabolism treat parkinsons?
Inhibit MAO-B and COMT Leads to increased synaptic concentrations.
How does surgery treat parkinson’s.
Deep brain sensitisation –> depolarisation block Surgical ablation.
