Parkinsons Disease Lecture 25

Question 1

What are the symptoms of Parkinsons Disease?

Answer 1

Tremors - mainly occur when resting Rigid muscles –> difficult to move (walking, writing, speech) Bradykineasia: hard to initiate and execute movement

Question 2

How is Parkinsons Disease degenerative?

Answer 2

Up to 2% of >65s affected Causes a decrease in the quality of life –> increased chance of dementia and death

Question 3

Define an ideopathic disease?

Answer 3

Of unknown cause

Question 4

Although parkinson’s is ideopathic what are the likely causes?

Answer 4

Combination of genetics and environment Symptomatic parkinsons can be post viral or drug related

Question 5

What is the biochemical / pathological basis of parkinsons

Answer 5

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

Question 6

What are the differences in the SNpc in the disease compared to normal?

Answer 6

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)

Question 7

What are the consequences of Parkinsons Disease?

Answer 7

D1 (G_alpha_s) and D2 (G_alpha_i) receptors are required for movement initiation. –> decreased feedback to thalamus

Question 8

Describe the histopathology of the disease

Answer 8

Loss of cells in the substantia nigra Lewy bodies are produced, containing lipds, proteins and alpha-synuclein (leads to aggregation, ubiquitin)

Question 9

What is the purpose of synuclein?

Answer 9

Normally regulates dopaminergic neurotransmission and synaptic vesicle pools, protects nerve terminal from injury

Question 10

What does the presence of Lewy bodies suggest?

Answer 10

A build up of toxins –> cell death (5% per decade)

Question 11

What are the inheritable effects of Parkinsons?

Answer 11

Production of Lewy bodies –> pathogenesis, causes a change in the ubiquitin-proteasomal pathway

Question 12

Describe the ubiquitin-proteasomal pathway enzymes:

Answer 12

Leads to protein degradation - Ubiquitin is the signalling molecule which signals for degradation. Turns it into a heritable disease

Question 13

What is the normal cause of cell death

Answer 13

Question 14

What happens to synuclein in the onset of parkinsons disease?

Answer 14

Acquires toxic properties. This causes misfolding in the ER –> disruption of organelles –> disruption of function

Question 15

What are the four therapy stategies for treating parkinson’s disease?

Answer 15

Drugs that replace dopamine –> increased synthesis Drugs that mimic dopamine Drugs which reduce dopamine metabolism Surgery

Question 16

How is dopamine usually synthesised

Answer 16

Tyrosine –> DOPA –> dopamine Tyrosine hydroxylase is the rate limiting enzyme

Question 17

What drugs are used to replace dopmaine.

Answer 17

L-DOPA because it increases dopamine synthesis –> increased release whilst ignoring the rate limiting enzyme.

Question 18

What are the problems with L-dopa therapy?

Answer 18

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

Question 19

What are possible ways to improve L-dopa therapy?

Answer 19

-Inhibit peripheral DOPA decarboxylase in order to increase the dopamine enetering the brain - Block peripheral DOPA receptors - Inhibit dopamine metabolism - Delay use

Question 20

How do drugs which mimic dopamine treat parkinsons?

Answer 20

Dopamine receptor agonists –> can still be used when the dopaminergic neurons are lost

Question 21

How do drugs which reduce dopamine metabolism treat parkinsons?

Answer 21

Inhibit MAO-B and COMT Leads to increased synaptic concentrations.

Question 22

How does surgery treat parkinson’s.

Answer 22

Deep brain sensitisation –> depolarisation block Surgical ablation.